Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Final Monograph for OTC Nasal Decongestant Drug Products

SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule

in the form of a final monograph establishing conditions under which

over-the-counter (OTC) nasal decongestant drug products (drug products

used to relieve nasal congestion caused by acute or chronic rhinitis)

are generally recognized as safe and effective and not misbranded. FDA

is issuing this final rule after considering public comments on the

agency's proposed regulation, which was issued in the form of a

tentative final monograph, and all new data and information on nasal

decongestant drug products that have come to the agency's attention.

Also, this final rule amends the regulation that lists nonmonograph

active ingredients by adding those OTC nasal decongestant ingredients

that have been found to be not generally recognized as safe and

effective and that were not previously listed in the regulation. This

final monograph is part of the ongoing review of OTC drug products

conducted by FDA.

EFFECTIVE DATE: August 23, 1995.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug

Evaluation and Research (HFD-810), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: 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, together with the recommendations of the

Advisory Review Panel on OTC Cold, Cough, Allergy, Bronchodilator, and

Antiasthmatic Drug Products (Cough-Cold Panel), which was the advisory

review panel responsible for evaluating data on the active ingredients

in these drug classes. Interested persons were invited to submit

comments by December 8, 1976. Reply comments in response to comments

filed in the initial comment period could be submitted by January 7,

1977.

In accordance with Sec. 330.10(a)(10), the data and information

considered by the Cough-Cold Panel were put on display in the Dockets

Management Branch (HFA-305), Food and Drug Administration, rm. 1-23,

12420 Parklawn Dr., Rockville, MD 20857, after deletion of a small

amount of trade secret information.

The agency's proposed regulations, in the form of tentative final

monographs, for OTC cold, cough, allergy, bronchodilator, and

antiasthmatic drug products were issued in the following segments:

Anticholinergics and expectorants, bronchodilators, antitussives, nasal

decongestants, antihistamines, and combinations. The fourth segment,

the tentative final monograph for OTC nasal decongestant drug products,

was published in the Federal Register of January 15, 1985 (50 FR 2220).

Interested persons were invited to file by May 15, 1985, written

comments, objections, or requests for oral hearing before the

Commissioner of Food and Drugs regarding the proposal. Interested

persons were invited to file comments on the agency's economic impact

determination by May 15, 1985. New data could have been submitted until

January 15, 1986, and comments on the new data until March 17, 1986.

In the Federal Register of June 19, 1992 (57 FR 27658), FDA

published a notice of proposed rulemaking to amend the tentative final

monograph for OTC nasal decongestant drug products to modify the drug

interaction precaution statement as follows:

Drug interaction precaution. Do not take this product if you are

taking a prescription drug containing a monoamine oxidase inhibitor

(MAOI) (certain drugs for depression or psychiatric or emotional

conditions), without first consulting your doctor. If you are

uncertain whether your prescription drug contains an MAOI, consult a

health professional before taking this product.

In the Federal Register of July 30, 1992 (57 FR 33663), FDA

published a correction to change the wording of the first sentence of

the statement from, ``Do not take * * *'' to ``Do not use * * *.'' In

the Federal Register of August 6, 1992 (57 FR 34734), the agency

extended the comment period to October 5, 1992, to obtain additional

comments on whether the drug interaction precaution statement should be

expanded to include MAO B drugs, such as selegiline. The agency asked

whether the proposed drug interaction precaution statement should be

expanded to read:

Drug interaction precaution. Do not use this product if you are

taking a prescription drug containing a monoamine oxidase inhibitor

(MAOI) (certain drugs for depression, psychiatric or emotional

conditions, or Parkinson's disease), without first consulting your

doctor. If you are uncertain whether your prescription drug contains

an MAOI, consult a health professional before taking this product.

The agency invited comments and information on interactions between

selegiline and sympathomimetic amines and asked whether, from a public

health perspective, it would be appropriate to expand the drug

interaction precaution statement, as indicated. Final agency action

occurs with the publication of this final monograph, which is the final

rule establishing a monograph for OTC nasal decongestant drug products

(see comment 22 in section I.E. of this document.)

The Advisory Review Panel on OTC Oral Cavity Drug Products (Oral

Cavity Panel) reviewed safety and effectiveness data on two oral nasal

decongestant ingredients, phenylephrine hydrochloride and

phenylpropanolamine hydrochloride (in lozenge form), and classified

these nasal decongestants in Category III in its report on OTC oral

health care drug products published in the Federal Register of May 25,

1982 (47 FR 22920). In the tentative final monograph for OTC oral

health care anesthetic/analgesic, astringent, debriding agent/oral

wound cleanser, and demulcent drug products published in the Federal

Register of January 27, 1988 (53 FR 2448), the agency referred the data

on these two oral nasal decongestant ingredients to the rulemaking for

OTC nasal decongestant drug products because most of the nasal

decongestant ingredients had been reviewed earlier and more extensively

by the Cough-Cold Panel. In this final rule, phenylephrine

hydrochloride for use as an oral nasal decongestant, which would

include use in a lozenge dosage form, is a monograph ingredient.

However, because of still unresolved safety issues concerning

phenylpropanolamine preparations, the agency is deferring action on

this drug. (See the Federal Register of January 15, 1985, 50 FR 2220 at

2221.) Therefore, phenylpropanolamine preparations will not be

categorized or further discussed in this document.

Propylhexedrine was formerly a scheduled drug both domestically and

internationally, but had an exclusion under 21 CFR 1308.22 that allowed

it to be sold OTC in the United States in inhaler products. In

September 1990, the 27th World Health Organization (WHO) Expert

Committee on Drug Dependence examined the international scheduling of

propylhexedrine. Based on new data, the Expert Committee recommended to

WHO that propylhexedrine be removed from international control. On June

10, 1991, the United States was notified that propylhexedrine had been

decontrolled internationally, thus obviating the need for domestic

control. The Drug Enforcement Administration issued a final rule in the

Federal Register of December 3, 1991 (56 FR 61372) to remove

propylhexedrine from the schedules of the Controlled Substances Act.

The ingredient l-desoxyephedrine is currently a scheduled drug in

the United States. However, a specific marketed inhaler product

containing this topical nasal decongestant ingredient has an exclusion

that allows it to be sold OTC in the United States (see 21 CFR

1308.22). Thus, this ingredient for topical use in an inhaler dosage

form could be included in this final monograph (See paragraph 19 in

section II of this document.)

The agency's final rule, in the form of a final monograph, for OTC

cold, cough, allergy, bronchodilator, and antiasthmatic drug products

is also being published in segments. Final agency action on all OTC

nasal decongestant drug products, except those containing

phenylpropanolamine, occurs with the publication of this final

monograph, which establishes Secs. 341.3(f) and (g), 341.20, and 341.80

for OTC nasal decongestant drug products in part 341 (21 CFR part 341).

Combination drug products containing nasal decongestant ingredients are

addressed in the tentative final monograph on OTC combination cough-

cold drug products, which was published in the Federal Register of

August 12, 1988 (53 FR 30522). A final rule for those combination

products will be published in a future issue of the Federal Register.

The OTC drug procedural regulations (21 CFR 330.10) provide that

any testing necessary to resolve the safety or effectiveness issues

that formerly resulted in a Category III classification, and submission

to FDA of the results of that testing or any other data, must be done

during the OTC drug rulemaking process before the establishment of a

final monograph. Accordingly, FDA does not use the terms ``Category I''

(generally recognized as safe and effective and not misbranded),

``Category II'' (not generally recognized as safe and effective or

misbranded), and ``Category III'' (available data are insufficient to

classify as safe and effective, and further testing is required) at the

final monograph stage. In place of Category I, the term ``monograph

conditions'' is used; in place of Category II or III, the term

``nonmonograph conditions'' is used.

As discussed in the proposed rule on OTC nasal decongestant drug

products (50 FR 2220), the agency advised that the conditions under

which the drug products that are subject to this monograph will be

generally recognized as safe and effective and not misbranded

(monograph conditions) will be effective 12 months after the date of

publication in the Federal Register. Therefore, on or after August 23,

1995, no OTC drug product that is subject to the monograph and that

contains a nonmonograph condition, i.e., a condition that would cause

the drug to be not generally recognized as safe and effective or to be

misbranded, may be initially introduced or initially delivered for

introduction into interstate commerce unless it is the subject of an

approved application or abbreviated application (hereinafter called

application). Further, any OTC drug product subject to this monograph

that is repackaged or relabeled after the effective date of the

monograph must be in compliance with the monograph regardless of the

date the product was initially introduced or initially delivered for

introduction into interstate commerce. Manufacturers are encouraged to

comply voluntarily with the monograph at the earliest possible date.

In response to the proposed rule on OTC nasal decongestant drug

products, 11 drug manufacturers, 1 drug manufacturers' association, 1

health care professional, and 11 consumers submitted comments. Copies

of the comments received are on public display in the Dockets

Management Branch (address above). Any additional information that has

come to the agency's attention since publication of the proposed rule

is also on public display in the Dockets Management Branch.

In proceeding with this final monograph, the agency has considered

all comments and objections, and the changes in the procedural

regulations.

All ``OTC Volumes'' cited throughout this document refer to the

submissions made by interested persons pursuant to the call-for-data

notice published in the Federal Register of August 9, 1972 (37 FR

16029) or to additional information that has come to the agency's

attention since publication of the notice of proposed rulemaking. The

volumes are on public display in the Dockets Management Branch (address

above).

I. The Agency's Conclusions on the Comments

A. General Comments on OTC Nasal Decongestant Drug Products

1. One comment contended that OTC drug monographs are interpretive,

as opposed to substantive, regulations. The comment referred to

statements on this issue submitted earlier to other OTC drug rulemaking

proceedings.

The agency addressed this issue in paragraphs 85 through 91 of the

preamble to the procedures for classification of OTC drug products,

published in the Federal Register of May 11, 1972 (37 FR 9464 at 9471

to 9472); in paragraph 3 of the preamble to the tentative final

monograph for OTC antacid drug products, published in the Federal

Register of November 12, 1973 (38 FR 31260); and in paragraph 2 of the

preamble to the tentative final monograph for OTC cough-cold

combination drug products, published in the Federal Register of August

12, 1988 (53 FR 30522 at 30524). FDA reaffirms the conclusions stated

in those documents. Court decisions have confirmed the agency's

authority to issue substantive regulations by rulemaking. (See, e.g.,

National Nutritional Foods Association v. Weinberger, 512 F.2d 688,

696-98 (2d Cir. 1975) and National Association of Pharmaceutical

Manufacturers v. FDA, 487 F. Supp. 412 (S.D.N.Y. 1980), aff'd, 637 F.2d

887 (2d Cir. 1981).)

2. Two comments stated that nasal decongestants cause dependency

and should not be available OTC. One of the comments, from a physician,

observed that a relatively large number of individuals with upper

respiratory symptoms (often associated with allergic rhinitis) begin

taking nasal decongestants and find that the symptoms persist for

longer than 1 week and often persist for several months at a time.

Furthermore, if the individuals attempt to use nasal decongestants for

the duration of this period, there is a high likelihood that they will

develop a tolerance of the nasal mucosa to the decongestant effect of

the medication. When the individuals try to stop the medication, they

develop a significant obstructive congestion of the nasal mucosa from

which they only apparently find relief through continued use of the

medicine. Also, the medication appears to lose its effect, somewhat,

with continued use over a long period of time, thus requiring even more

frequent use. The comment stated this was particularly a problem with

nasal sprays and cited several patients who persisted in using OTC

nasal sprays every 2 hours or so despite intensive efforts by the

physician to discourage such use. The comment contended that easy

accessibility of these products, due to their OTC status, makes it

almost impossible to wean some patients from the use of nasal

decongestants. The second comment, from a consumer, opposed OTC use of

nasal decongestants because of experience in which a member of the

family became dependent on nasal decongestant sprays in order to

breathe.

The agency has reexamined the Cough-Cold Panel's discussion

regarding ``rebound congestion.'' The Cough-Cold Panel stated the

following:

Because of the remarkable degree of nasal decongestion which

follows topical application of these agents, there is the tendency

on the part of patients to administer nasal decongestants too

frequently and for too long a period of time. Continued and intense

drug-induced vasoconstriction can lead to rebound dilation of the

blood vessels as the drug effect subsides. This phenomenon, which

intensifies nasal congestion and perpetuates the rhinitis condition,

has been termed ``rebound congestion.'' This problem is minimized if

topically applied decongestants are administered in accordance with

label directions at recommended intervals for periods not exceeding

3 days. (See 41 FR 38312 at 38396.)

Although aware that continued use of nasal decongestant drugs might

result in rebound congestion, the Cough-Cold Panel thought that the

clinical and marketing data it reviewed showed these drugs to be safe

and effective when used according to label directions. Therefore, the

Cough-Cold Panel concluded that such drugs should be available for OTC

use and it recommended the following warning: ``Do not use this product

for more than 3 days. If symptoms persist, consult a physician'' (41 FR

38312 at 38423).

In the tentative final monograph, the agency concurred with the

Cough-Cold Panel's recommendations that all nasal drops, sprays, and

jellies, and propylhexedrine in inhalant form be labeled to limit use

to not more than 3 days so as to discourage prolonged use and that a

doctor should be consulted if symptoms persisted after 3 days of use.

(See Sec. 341.80 (c)(2)(iii)(a) and (c)(2)(vi) in 50 FR 2220 at 2239.)

The ingredient l-desoxyephedrine in inhalant form had to bear the same

warning except it stated 7 days instead of 3 days. (See

Sec. 341.80(c)(2)(ii) and discussion in 50 FR 2220 at 2225.)

In addition, the agency has reviewed comments to the Cough-Cold

Panel's report concerning rebound congestion and finds seven comments

from allergists who specifically mentioned oxymetazoline,

xylometazoline, naphazoline, or phenylephrine as causing rebound

congestion due to prolonged or excessive use (Ref. 1). Moreover, the

agency has reviewed adverse drug reaction reports for the years 1976 to

1993 and finds that the two most frequently reported adverse effects of

marketed OTC topical nasal decongestant drug products are rebound

congestion and drug dependence (Ref. 2).

The agency believes that the OTC availability of topical nasal

decongestants is beneficial to many consumers who seek temporary relief

from nasal congestion and concurs with the Cough-Cold Panel's

recommendations that these products can be safely used according to

label directions. The agency is concerned, however, in view of comments

submitted to this rulemaking and adverse drug reactions reported to

FDA, that consumers may not be adequately alerted and warned of the

problem of rebound congestion, which may be caused by prolonged or

excessive use of these preparations. Thus, the agency believes that the

3-day use warning should be expanded to explain to consumers the reason

for the 3-day limitation for use of topical nasal decongestants.

Therefore, in this final monograph the warning in

Sec. 341.80(c)(2)(iii)(A) for adults, in Sec. 341.80(c)(2)(viii) for

children under 12 years of age, and in Sec. 341.80 (c)(2)(v) and

(c)(2)(ix) for propylhexedrine in inhalant form for adults and

children, respectively, is expanded as follows: ``Do not use this

product for more than 3 days. Use only as directed. Frequent or

prolonged use may cause nasal congestion to recur or worsen. If

symptoms persist, consult a doctor.''

The agency concludes that these additions to the labeling included

in this final monograph will provide for the safe and effective use of

OTC topical nasal decongestant drugs.

References

(1) Comments No. C0026, C0077, C0092, C0095, C0118, C0120, C0130,

Docket No. 76N-0052, Dockets Management Branch.

(2) Department of Health and Human Services, Food and Drug

Administration, ``Spontaneous Reporting System, Line Listing of

Adverse Reports: Nasal-76-93,'' 1976-1993, in OTC Vol. 04NFM, Docket

No. 76N-052N, Dockets Management Branch.

3. Referring to the statements in the tentative final monograph for

OTC antihistamine drug products, ``* * * antihistamines did not reduce

nasal obstruction and therefore did not aid in sinus drainage. To the

contrary, the studies indicated that antihistamines may sometimes

further aggravate nasal obstruction'' (50 FR 2200 at 2203), one comment

expressed concern that FDA not use this statement as a basis for

disagreeing with the Cough-Cold Panel's Category I classification of

combinations containing an antihistamine and an oral nasal

decongestant.

In the tentative final monograph for OTC antihistamine drug

products (50 FR 2200 at 2203), the agency made the statements quoted

above as part of its discussion that antihistamines are ineffective for

the treatment of sinus congestion. It was not the agency's intent to

use the statements as a basis for disagreeing with combination drug

products containing an antihistamine and an oral nasal decongestant.

In the tentative final monograph for OTC cold, cough, allergy,

bronchodilator, and antiasthmatic combination drug products, the agency

agreed with the Cough-Cold Panel's Category I classification of

combinations containing an antihistamine and an oral nasal decongestant

(53 FR 30522 at 30539). In view of the data reviewed by the Cough-Cold

Panel that support combinations containing an antihistamine and an oral

nasal decongestant (41 FR 38312 at 38326) and the extensive data on

such combinations that are available to the agency, the agency

reiterates the Cough-Cold Panel's recommendation that combinations

containing an antihistamine and an oral nasal decongestant are safe,

effective, and rational.

B. Comments on Switching Prescription Nasal Decongestant Active

Ingredients to OTC Status

4. Several comments opposed the availability of oxymetazoline

hydrochloride and xylometazoline hydrochloride as OTC topical nasal

decongestants. The comments also opposed the availability of

pseudoephedrine hydrochloride and pseudoephedrine sulfate at dosage

levels twice as high as previously permitted for OTC use. The comments

expressed concern that these drugs could be dangerous or harmful to

many people, young and old alike. One comment felt that self-medicating

with nasal decongestants might cause damage to ``mucous-lined

passages'' and that consumers might not know if they have one of the

conditions (i.e., heart disease, high blood pressure, thyroid disease,

diabetes, or difficulty in urination due to enlargement of the prostate

gland) listed in the warnings for these products. Two comments approved

of FDA's requirement for warning information in labeling and supported

the OTC availability of these drugs. Another comment mentioned,

however, that many persons unfortunately do not or cannot read labels.

As discussed in the tentative final monograph, the agency reviewed

safety and effectiveness data on oxymetazoline hydrochloride,

xylometazoline hydrochloride, pseudoephedrine hydrochloride, and

pseudoephedrine sulfate and agreed with the Cough-Cold Panel that these

active ingredients could be generally recognized as safe and effective

for OTC use when appropriately labeled. (See 50 FR 2220 at 2222 to

2223, 2229 to 2230, and 2233 to 2234.) The comments did not submit any

data to show that these ingredients should not be available OTC.

To enhance the safe use of these ingredients, in the tentative

final monograph, the agency modified several of the Cough-Cold Panel's

recommendations regarding pseudoephedrine hydrochloride and

pseudoephedrine sulfate as oral nasal decongestants, and oxymetazoline

hydrochloride and xylometazoline hydrochloride as topical nasal

decongestants. For example, the agency reduced the maximum adult oral

dosage of pseudoephedrine preparations from 360 milligrams (mg) to 240

mg in 24 hours (50 FR 2229 to 2230). The agency also proposed that

topical nasal decongestant products containing oxymetazoline

hydrochloride and xylometazoline hydrochloride not be used in children

under 6 years of age unless recommended by a doctor (50 FR 2222 to

2223).

Regarding one comment's concern that self-medicating with OTC nasal

decongestants might cause damage to ``mucous-lined passages,'' the

comment did not explain its use of the term ``mucous-lined passages,''

nor did it submit any data to substantiate its claim that OTC nasal

decongestants at the recommended dosages can cause damage to ``mucous-

lined passages.'' Although frequent and prolonged use of topical nasal

decongestants may lead to rebound congestion (see comment 2 in section

I.A. of this document), the agency is unaware of possible long-term

damage to ``mucous-lined passages'' if a topical nasal decongestant

drug product is used for a short period of time and according to

directions. As the Cough-Cold Panel pointed out, the problem of rebound

congestion is not a factor with use of the orally administered nasal

decongestants (41 FR 38312 at 38397).

Regarding the comment's concern that consumers might not know if

they have one of the conditions listed in the warnings for these

products (i.e., heart disease, high blood pressure, thyroid disease,

diabetes, or difficulty in urination due to enlargement of the prostate

gland), the agency notes that there are additional warnings in the

monograph informing consumers that topical nasal decongestants should

not to be used for more than 3 days and that oral nasal decongestants

should not be used for more than 7 days, and if symptoms persist, to

consult a doctor. Because these products are intended to be used for a

limited time only, the agency believes that the risk of adverse effects

at the recommended oral or topical dosages is minimal. Moreover, the

agency believes that persons having most of the conditions listed in

the warning (heart disease, thyroid disease, diabetes, difficulty in

urination) would be aware of their condition (because of other apparent

symptoms) and be under medical treatment, and the warning instructs

them not to use the product unless directed by a doctor.

There is a concern, however, for individuals having certain

conditions that may have no apparent symptoms. High blood pressure is a

well-known example of such a disease. Persons with high blood pressure

may be unaware that they have the condition and may use a nasal

decongestant without being aware that the nasal decongestant drug can

affect the condition. Nasal decongestants and other sympathomimetic

drugs can produce a variety of adverse effects and should be used with

caution in individuals with high blood pressure (Refs. 1 and 2). Of the

estimated 58 million hypertensive individuals in the United States,

about 20 percent (approximately 11 million) do not know they have high

blood pressure (Ref. 3). If high blood pressure is not treated,

problems such as heart failure, stroke, and kidney disease may occur.

The agency believes that periodic medical examinations, high blood

pressure screening programs, and education are the most important tools

to detect undiagnosed hypertensive individuals. The agency encourages

consumers to take advantage of such programs to help minimize the risks

associated with undiagnosed high blood pressure.

Regarding the comment that many persons unfortunately do not or

cannot read labels, the agency notes that section 502(c) of the Federal

Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352(c)) requires that

a drug be labeled ``* * * in such terms as to render it likely to be

read and understood by the ordinary individual under customary

conditions of purchase and use.'' The labeling in this final monograph

is intended to meet this statutory requirement.

The safety and effectiveness data on oxymetazoline hydrochloride,

xylometazoline hydrochloride, pseudoephedrine hydrochloride, and

pseudoephedrine sulfate that were reviewed by the Cough-Cold Panel and

the agency support the agency's conclusion that these ingredients can

be generally recognized as safe and effective for OTC use when marketed

in accordance with the labeling and other conditions established in

this final monograph.

References

(1) Berkow, R., editor, ``The Merck Manual,'' 16th ed., Merck and

Co., Rahway, NJ, p. 192, 1992.

(2) ``Drug Evaluations Annual,'' American Medical Association,

Milwaukee, WI, pp. 407-408, 1991.

(3) Berkow, R., editor, ``The Merck Manual,'' 16th ed., Merck and

Co., Rahway, NJ, p. 419, 1992.

C. Comments on Specific OTC Nasal Decongestant Active Ingredients

5. One comment requested that the agency place camphor (0.1

percent), eucalyptus oil (0.025 percent), and menthol (0.05 percent) in

Category I as individual OTC topical/inhalant nasal decongestants for

use in a hot steam vaporizer; and place the ingredients camphor (4.73

to 5.3 percent), eucalyptus oil (1.2 to 1.3 percent), and menthol (2.6

to 2.8 percent) in Category I as individual OTC topical/inhalant nasal

decongestants for use in a chest rub ointment form. The comment

submitted three controlled clinical studies (CRD 83-10, CRD 82-10, and

CRD 82-09) and two pilot clinical studies (CRD 74-63A and CRD 75-39) of

the individual ingredients to support its request (Ref. 1). The first

study (CRD 83-10) concerned the single aromatics in steam from a

vaporizer. The other four studies concerned the single aromatics in

petrolatum applied to the chest and throat. In response to the agency's

concerns regarding the statistical analysis of study CRD 83-10 (Ref.

2), the comment provided a statistical reanalysis of the study (Ref.

3).

The agency has reviewed the data and determined that the clinical

studies do not support the reclassification of the individual

ingredients as requested by the comment. Although one study (CRD 83-10)

shows some statistically significant evidence of the effectiveness of

camphor, eucalyptus oil, and menthol as topical/inhalant nasal

decongestants administered by steam vaporization, there are certain

statistical problems with the data that make the results questionable.

Although the statistical reanalysis provides some statistical evidence

of efficacy, the agency concludes that stronger evidence of efficacy

from a second study is needed (Ref. 4). The other four studies (CRD 82-

10, CRD 82-09, CRD 74-63A, and CRD 75-39) are insufficient to

demonstrate the effectiveness of camphor, eucalyptus oil, and menthol

as individual topical/inhalant nasal decongestants in a chest rub

ointment form.

Study CRD 83-10 was designed to determine the individual topical/

inhalant nasal decongestant effect of camphor, eucalyptus oil, and

menthol vaporized in steam compared to unmedicated steam. In this

single-blind, parallel study, 234 subjects with acute upper respiratory

tract infection were equally divided into 4 treatment groups (vaporized

camphor, eucalyptus oil, menthol, or steam control). Nasal airway

resistance was measured with a rhinomanometer before treatment, every

15 minutes (min) for the first hour and every 30 min for the second

hour. The investigator reported that when the individual observation

time points were examined, the results indicated that each ingredient

was significantly more effective in reducing nasal congestion than

steam alone at each 15-min interval over the first hour (all p

0.02) and over the entire 2-hour exposure period.

Although the comment claimed that study CRD 83-10 showed each

active ingredient to be statistically better than placebo (steam)

control, the agency has determined that the data and the reanalysis of

study CRD 83-10 alone do not provide adequate support for the monograph

status of camphor, eucalyptus oil, and menthol as individual topical/

inhalant nasal decongestant ingredients for several reasons. First,

there was an improper use of baseline values; for example, the baseline

values were measured 15 min and 0 min before treatment, but only the 0-

minute measurement was used as the baseline value. Conversely, in study

CRD 82-10, the baseline values were taken as the average of 15- and 0-

min pretreatment measurements. Second, the use of the Bartlett's test

to verify the assumption of homogeneity of the variances in the

logarithm-transformed data demonstrated that the homogeneity of the

variances was found to be acceptable for only the first 60 min, i.e.,

variances among treatment groups were not significantly different for

the periods of 15, 30, 45, and 60 min. However, statistically

significant differences were found at 90 min, 120 min, and overall,

with the steam control group showing an unacceptable consistently

higher variance than the active ingredient treatment groups. Third, the

reanalysis of the logarithm-transformed rhinomanometer measurement data

by the Kruskal-Wallis test (a nonparametric test) showed that the

active ingredients were statistically better than the steam control

group only within the first hour of the study and not significantly

better than the steam control group after one hour. These weak findings

would be further weakened if adjustment for p-value for multiple

testing of time points were made.

Should another study be done, a repeated measurement analysis

(i.e., an overall analysis) of the rhinomanometer data needs to

consider the increase in variance over all time points to remedy the

problem of repeated testings. Further, if variances in results increase

over the time period in an additional study, the reason for this

occurrence needs to be addressed.

Study CRD 82-10 compared the nasal decongestant effects of the

individual ingredients camphor 5.2 percent, eucalyptus oil 1.3 percent,

and menthol 2.8 percent in petrolatum against a petrolatum placebo in

40 subjects per group with acute coryzal rhinitis (common cold) using a

randomized parallel design. The investigator reported that there were

no statistically significant differences between treatments with

respect to objectively measured nasal congestion for the total study

population. Study CRD 82-09 used the same protocol as CRD 82-10, with

39 to 42 subjects per group. This study also did not show any

statistically significant differences between test and control

treatments. In conclusion, both studies, CRD 82-10 and CRD 82-09,

provide no statistically significant data that the individual active

ingredients were better than petrolatum control in reducing nasal

congestion in subjects with acute coryzal rhinitis.

Regarding the two pilot studies (CRD 74-63A and CRD 75-39), the

agency notes that both studies used the same protocol. The studies were

randomized crossover studies using subjects with colds. Comparisons

were made by objective measurement of nasal airway resistance using

anterior rhinomanometry. Study CRD 74-63A compared a commercial product

containing a combination of volatile aromatic oils with the following

individual ingredients: Eucalyptus oil 1.33 percent in a petrolatum

base, turpentine oil 5.12 percent in a petrolatum base, and petrolatum

(placebo). Study CRD 75-39 compared the nasal decongestant effects of a

commercial product containing a combination of volatile aromatic oils

with the following individual ingredients: Camphor 4.7 percent in a

petrolatum base, menthol 2.6 percent in a petrolatum base, and

petrolatum (placebo). A summary statistical analysis of studies CRD 74-

63A and CRD 75-39, prepared by the comment's statistician (Ref. 2),

states that these studies show no statistical advantages for the

components over petrolatum and that the absence of statistical

significance in these studies is not unexpected because of the small

sample sizes of the treatment groups. Furthermore, significant residual

effects were detected in the data from these studies, indicating that

the crossover model was inappropriate. The agency concludes that

studies CRD 74-63A and CRD 75-39 do not provide adequate data to

demonstrate the effectiveness of camphor, eucalyptus oil, and menthol

as individual topical/inhalant active ingredients when administered in

a chest rub ointment form.

In conclusion, the submitted data are insufficient to generally

recognize camphor, eucalyptus oil, and menthol as safe and effective as

individual topical/inhalant nasal decongestant active ingredients,

either in petrolatum applied to the chest and throat or in a hot steam

vaporizer. Therefore, at this time, these ingredients for these uses

are not being included in the final monograph for OTC nasal

decongestant drug products. Combination products containing these

ingredients are discussed in the tentative final monograph for OTC

cough-cold combination drug products, published in the Federal Register

of August 12, 1988 (53 FR 30522). In that tentative final monograph

nasal decongestant use was discussed in comment 59 (53 FR 30522 at

30550), and antitussive use was discussed in comments 56 and 57 (53 FR

30522 at 30547 to 30548). These combination products will be addressed

in the final monograph for OTC cough-cold combination drug products,

which will be published in a future issue of the Federal Register.

The agency's detailed comments and evaluations of the data are on

file in the Dockets Management Branch (Ref. 3).

References

(1) ``VapoRub,'' Vol. 1, Richardson-Vicks, Inc., submitted as part

of Comment No. C0212, Docket No. 76N-052N, Dockets Management

Branch.

(2) Letter from W. E. Gilbertson, FDA, to E. J. Hanus, Richardson-

Vicks, Inc., coded as LET095, Docket No. 76N-052N, Dockets

Management Branch.

(3) Letter from E. J. Hanus, Richardson-Vicks, Inc., to W. E.

Gilbertson, FDA, coded as LET096, Docket No. 76N-052N, Dockets

Management Branch.

(4) Letter from W. E. Gilbertson, FDA, to E. J. Hanus, Richardson-

Vicks, Inc., coded as LET109, Docket No. 76N-052N, Dockets

Management Branch.

6. One comment submitted data (Refs. 1 and 2) to support the

effectiveness of ephedrine and its salts as an oral nasal decongestant.

The data consisted of four studies (CRD 78-04, CRD 78-06, CRD 78-26,

and CRD 78-27) (Refs. 3 through 6) in which the data were pooled and

analyzed as one study; three single-investigator studies (CRD 74-9, CRD

74-57, and CRD 76-61) (Refs. 7, 8, and 9); and four articles from the

scientific literature (Refs. 10 through 13). Additional statistical

information (Ref. 2) was provided by the comment in response to the

agency's request (Ref. 14). The comment also noted that the agency

concluded in the tentative final monograph for OTC bronchodilator drug

products (47 FR 47520 at 47527, October 26, 1982) that ephedrine and

its salts at a 25-mg oral dose as a bronchodilator are safe for OTC

use. The comment requested that ephedrine and its salts be placed in

Category I for oral nasal decongestant use at a dosage of 8 to 25 mg

every 4 hours, not to exceed 75 mg in 24 hours.

The pooled study (studies CRD 78-04, CRD 78-06, CRD 78-26, and CRD

78-27) (Refs. 3 through 6) involved a total of 445 subjects obtained by

4 different investigators. These were parallel studies with 60 subjects

participating in CRD 78-04, 54 subjects in CRD 78-06, 202 subjects in

CRD 78-26, and 129 subjects in CRD 78-27. Each study group was

subdivided into three subgroups. The subjects in each subgroup received

a single dose of aqueous solution containing ephedrine sulfate 8 mg/

dose, ephedrine sulfate 12 mg/dose, or an aqueous placebo. Nasal airway

resistance was measured by Vick's Rhinomanometer at 30, 60, 90, 120,

and 180 min after the dose was given.

In analyzing the data in the pooled study, the agency noted that

out of the four studies, there were only sporadic statistically

significant rhinomanometer data differences in favor of ephedrine 12 mg

over placebo in Study CRD 78-26 (Ref. 5). For subjective subject

ratings of nasal congestion, there were only sporadic statistically

significant differences in favor of ephedrine 12 mg over placebo in

Study CRD 78-26. With sample sizes ranging from 17 to 45 subjects per

treatment group, there should be adequate statistical power to detect a

significant clinical difference if it exists. However, both

rhinomanometer measurements and subject ratings of nasal congestion

data failed to clearly differentiate ephedrine from placebo in these

studies.

In the pooled data analysis, significant treatment by center

interaction was found in 3 of the 5 time-point analyses (p

0.15). Six of 25 time-point analyses (24 percent) showed

that placebo was the same or better than ephedrine. A statistical

reanalysis of the data (Ref. 2) did not establish any statistical

evidence, either in the pooled data or in any of the individual

studies, that ephedrine is superior to the placebo control in reducing

nasal congestion. The agency also notes that this reanalysis of the

data using the Kruskal-Wallis test (a nonparametric version of ``one-

way'' analysis of variance) does not remove the issue of center

interaction. Further, the mathematical model that was used to analyze

the rhinomanometer data provides an extremely low R-square value.

Hence, the agency considers these findings as casting doubt on the

poolability of these efficacy data and believes that conclusions should

be drawn based on the results from individual studies. Therefore, the

agency concludes that the data in the pooled study fail to provide

substantive statistical evidence of effectiveness.

The single-investigator studies (CRD 74-9, CRD 74-57, and CRD 76-

61) (Refs. 7, 8, and 9) involved a total of 316 subjects. Study CRD 74-

57 (Ref. 8) did not show any statistically significant difference

between ephedrine and placebo. This parallel-design, double-blind,

computer-randomized study used nasal airway flow rate measurements to

compare the nasal decongestant effect of solutions of ephedrine sulfate

8 mg/30 milliliters (mL), ephedrine sulfate 16 mg/30 mL,

phenylpropanolamine hydrochloride 37.5 mg/30 mL, and a 30 mL placebo

vehicle solution containing no active ingredient. Two doses were given,

4 hours apart. A total of 189 subjects with nasal congestion due to

coryza was divided among the 4 treatment groups. The results showed

that the phenylpropanolamine solution had the greatest effect on

increasing nasal airflow when compared with both doses of ephedrine and

the placebo. Both doses of ephedrine produced significantly greater

flow than placebo overall, but not at any of the individual time

intervals. The effect of ephedrine 16 mg/30 mL also approached

significance at the final evaluation (2 hours after the second dose).

There were no significant differences noted in the subjective

evaluation of runny nose, post-nasal drip, watery eyes, and number of

sneezes. However, the use of the ephedrine 16 mg/30 mL solution seemed

to be beneficial in reducing the number of ``nose blows.''

Study CRD 74-9 (Ref. 7) also did not demonstrate any statistically

significant difference between ephedrine and placebo. This was a

parallel-design study employing 86 subjects with nasal congestion due

to coryza. The subjects were divided into 3 subgroups with 29 subjects

receiving ephedrine sulfate 8 mg/30 mL (aqueous vehicle), 29 subjects

receiving phenylpropanolamine hydrochloride 25 mg/30 mL (aqueous

vehicle), and 28 subjects receiving 30 mL of the aqueous vehicle alone.

It was noted in this study that sorbitol was added to the test solution

given to the first 34 subjects. However, when 3 subjects (1 in each of

the 3 treatment groups) experienced intestinal distress, the remaining

52 subjects were given an aqueous test solution without the sorbitol.

The agency notes that, in general, no clinical conclusions can be

derived from this study because of the differing results obtained

between the sorbitol and nonsorbitol-containing test solutions.

Only one study, CRD 76-61 (Ref. 9), showed some favorable results.

This study was a double-blind, computer-randomized crossover study

involving 41 subjects having nasal congestion due to coryza. Eighteen

subjects received 8 mg of ephedrine sulfate and 23 subjects received 12

mg of ephedrine sulfate on one of two test days, both administered in

30 mL of aqueous vehicle. All 41 subjects received aqueous vehicle

placebo on the other test day. Nasal airway resistance was used as an

objective measure of nasal congestion and changes therein. Resistance

was measured by Vick's Rhinomanometer before treatments were

administered and at 30, 60, 90, 120, and 180 min after treatments,

which were 24 hours apart. Subjective ratings were also recorded before

each measurement. Subjectively, subjects using the 8-mg and 12-mg doses

of ephedrine sulfate perceived an improvement in nasal decongestion to

a statistically significant extent, but the comparisons with placebo

results were not significant. As determined by nasal airway resistance

measurements, both the 8-mg and 12-mg doses of ephedrine sulfate

decreased the nasal congestion of subjects to a statistically

significant extent overall, in comparison with the results obtained

with the placebo. However, the agency considers the results of the

study to be inconsistent because the ephedrine 8-mg group obtained some

favorable results over placebo at 60 min after treatment, but the

ephedrine 12-mg group obtained only sporadically favorable results. In

addition, the 12-mg group obtained significant results only within the

first hour after treatment, while the 8-mg group did not obtain

significant results until 1 hour after treatment. These discrepancies

are not adequately explained. The agency believes that the findings in

both the pooled studies (Refs. 3 through 6) and the individual study

CRD 76-61 (Ref. 9) would be further weakened if adjustments for

multiple testings of hypotheses were made.

With regard to the four articles (Refs. 10 through 13) from the

literature, the agency finds that these articles are not supportive of

either the pooled study or the individual studies. The McLaurin,

Shipman, and Rosedale study (Ref. 10) was reviewed by the Cough-Cold

Panel, which found that it did not contain any conclusive data to

support claims of nasal decongestant effectiveness for 8 to 12 mg

ephedrine doses contained in OTC drug products (41 FR 38312 at 38408).

Although the Cough-Cold Panel stated that the study demonstrated nasal

decongestant effectiveness of orally administered ephedrine sulfate in

doses of 25 mg, the agency considers the study inadequate to establish

effectiveness because it was not controlled. The study by Gowen and

Nedzel (Ref. 11) and the study by Mothersill (Ref. 12) are not adequate

because the results were subjective and ephedrine was not studied

alone, but in combination with other active ingredients. Likewise, the

Aschan study (Ref. 13) also was not a single active ingredient study.

Although safety is not a problem, as the comment noted, based on

the lack of adequate data to demonstrate effectiveness, ephedrine and

its salts are not being included as oral nasal decongestant ingredients

in this final monograph. The agency's detailed comments and evaluation

of the data are on file in the Dockets Management Branch (Ref. 15).

References

(1) Comment No. C0214, Docket No. 76N-052N, Dockets Management

Branch.

(2) Comment No. SUP003, Docket No. 76N-052N, Dockets Management

Branch.

(3) Hayes, S.L., ``Multicenter-Pooled Study,'' draft of unpublished

study (CRD 78-04), in Comment No. C0214, Docket No. 76N-052N,

Dockets Management Branch.

(4) Fulco, O.J., ``Multicenter-Pooled Study,'' draft of unpublished

study (CRD 78-06), in Comment No. C0214, Docket No. 76N-052N,

Dockets Management Branch.

(5) doPico, G.A., ``Multicenter-Pooled Study'', draft of unpublished

study (CRD 78-26), in Comment No. C0214, Docket No. 76N-052N,

Dockets Management Branch.

(6) Diamond, P.H., ``Multicenter-Pooled Study,'' draft of

unpublished study (CRD 78-27), in Comment No. C0214, Docket No. 76N-

052N, Dockets Management Branch.

(7) Connell, J.T., ``Ephedrine, Phenylpropanolamine, and Placebo

Comparisons,'' draft of unpublished study (CRD 74-9), in Comment No.

C0214, Docket No. 76N-052N, Dockets Management Branch.

(8) Connell, J.T., ``Nasal Airway Flow Rate Measurement

Comparisons,'' draft of unpublished study (CRD 74-57), in Comment

No. C0214, Docket No. 76N-052N, Dockets Management Branch.

(9) doPico, G.A., ``Ephedrine and Placebo Comparison,'' draft of

unpublished study (CRD 76-61), in Comment No. C0214, Docket No. 76N-

052N, Dockets Management Branch.

(10) McLaurin, J.W., W.F. Shipman, and R. Rosedale, ``Oral

Decongestants--A Double Blind Comparison Study of the Effectiveness

of Four Sympathomimetic Drugs: Objective and Subjective,''

Laryngoscope, 71:54-67, 1961.

(11) Gowen, G.H., and A.J. Nedzel, ``Effectiveness of the Oral

Administration of Ephedrine in the Common Cold,'' Illinois Medical

Journal, 71:132-136, 1937.

(12) Mothersill, M.H., ``Treatment of Hay Fever with a Combination

of a Sympathomimetic and an Antihistaminic Drug,'' Annals of

Allergy, 8:223-228, 1950.

(13) Aschan, G., ``Decongestion of Nasal Mucous Membranes by Oral

Medication in Acute Rhinitis,'' Acta Otolaryng, 77:433-438, 1974.

(14) Letter from W.E. Gilbertson, FDA, to E.J. Hanus, Richardson-

Vicks, coded LET020, Docket No. 76N-052N, Dockets Management Branch.

(15) Letter from W.E. Gilbertson, FDA, to E.J. Hanus, Richardson-

Vicks, coded LET107, Docket No. 76N-052N, Dockets Management Branch.

7. One comment submitted a citizen petition requesting that 10 mg

menthol in a solid dosage form for use as a topical/inhalant nasal

decongestant be included in the final monograph (Refs. 1 and 2). The

comment requested the following directions for use for the 10-mg

menthol solid dosage form: ``Adults and children 3 to under 12 years of

age: dissolve one solid dosage form in the mouth every 2 hours as

needed. Do not chew. Children under 3 years of age: consult a doctor.''

The agency has reviewed the petition and other information and

finds the data supportive of the effectiveness of a 10-mg menthol

lozenge as a single dose for topical nasal decongestant use. However,

the agency has concluded that the data are not sufficient to include

the ingredient in the monograph for the reasons discussed below.

The petition included a double-blind, randomized, placebo-

controlled, parallel-design, single-dose study of a 10-mg menthol

lozenge in subjects with viral rhinitis. The subjects were at least 18

years of age with symptoms of stuffy nose, runny nose, sneezing, and/or

cough of no more than 48 hours duration. The objective of the study was

to determine if statistically significant decreases in nasal airway

resistance occurred at specific intervals after administration of the

drug. Posterior rhinometry measurements were correlated with the

subjects' subjective ratings of decongestant activity. Measurements of

nasal flow/resistance were made 5 min before and immediately prior (0

min) to administration of the test lozenge and at 15, 30, 60, 90, and

120 min after dosing. The measurement immediately prior to dosing was

used as the baseline measurement. The nasal/flow resistance data were

analyzed by a repeated measures analysis of variance with 6 time points

(baseline, 15, 30, 60, 90, and 120 min) as the repeat factor. Changes

from the baseline at the post-treatment time points were also analyzed

using a one-way analysis of variance.

The agency notes that the protocol for this study is similar to

that proposed by the Panel (41 FR 38312 at 38415). The Cough-Cold Panel

recommended that a study to show effectiveness of a nasal decongestant

drug should be a double-blind, placebo-controlled assessment of the

drug's ability to decrease nasal airway resistance. The Cough-Cold

Panel also considered subjective assessment by the subjects to be

desirable. The Cough-Cold Panel stated that where rebound congestion

with repeated use is a concern, labeling should specify short-term use

in providing temporary relief of symptoms. The Cough-Cold Panel

recommended that specific data be obtained by testing the nasal

decongestant in the concentrations and maximal dosage frequencies to be

recommended for periods of at least 1 week to address the incidence and

severity of a drug-induced increase in nasal airway resistance. The

Cough-Cold Panel required two positive studies based on the results of

two different investigators or laboratories to show effectiveness.

The agency finds that the results of the study suggest that 10 mg

menthol in a solid dosage form is effective in the relief of nasal

congestion due to viral rhinitis. However, the repeated measures

analysis of variance results were not informative because they included

the baseline levels in the analysis. By deleting the baseline levels

from the analysis, the agency notes that the multivariate analyses of

the data using the Statistical Analysis System Institute statistical

system showed a significant treatment effect but nonsignificant time

and treatment by time interaction. The results of the study support a

2-hour duration of action from a single dose. However, because the

proposed directions for the product include multiple doses (i.e.,

``every 2 hours as needed''), another study involving multiple doses is

needed to support effectiveness. The study needs to be done using the

same dosage with the drug given at the same time intervals as proposed

for the label directions. A 3-day study is necessary to show

effectiveness as a nasal decongestant if the product will be indicated

for colds and 7 days if indicated for allergies.

The agency notes that the petition did not address the potential

problem of rebound congestion occurring with repeated use of menthol

lozenges. In the tentative final monograph (50 FR 2220 at 2233), the

agency discussed the occurrence of rebound congestion resulting from

topical nasal decongestants in a lozenge or mouthwash dosage form. The

agency stated that when ingredients such as menthol are administered in

the form of lozenges, rebound is unlikely to occur and that it may be

more appropriate to use a 7-day warning, i.e., ``Do not use this

product for more than 7 days,'' rather than a 3-day warning. However,

because such lozenges are not included in this final monograph, such a

warning requirement is not applicable at this time. The agency believes

that the potential for rebound congestion to occur should be studied in

any multi-dose study, such as the study discussed above, involving

topical nasal decongestants in a lozenge or mouthwash dosage form to

rule out the potential for rebound congestion to occur and to determine

which warning statement would be appropriate to use for the product.

Based on the above information, the agency is not including 10 mg

menthol in solid dosage form as a topical nasal decongestant in this

final monograph. The agency's detailed comments and evaluations on the

data are on file in the Dockets Management Branch (Ref. 3).

References

(1) Comment No. CP00010, Docket No. 76N-052N, Dockets Management

Branch.

(2) Letter from C.A. Sloughfy, Jr., Beecham Products, to J.R.

Gebert, FDA, coded as LET101, Docket No. 76N-052N, Dockets

Management Branch.

(3) Letter from W.E. Gilbertson, FDA, to B. Misek, Beecham Products,

coded as LET108, Docket No. 76N-052N, Dockets Management Branch.

8. One comment objected to the agency's proposal in the tentative

final monograph to restrict to professional labeling the use of

oxymetazoline hydrochloride in children under 6 years of age because

this action would exclude such use from general consumer labeling.

Referring to studies that showed substantial differences when

oxymetazoline was given to dogs intranasally and intravenously to

elicit a cardiovascular effect (i.e., increase in blood pressure), the

comment stated that the amount of oxymetazoline required to elicit any

systemic effect by the intranasal route would be virtually unachievable

with marketed products. Thus, according to the comment, it would be

extremely unlikely that a child could receive a dose of oxymetazoline

that would have systemic effects. In addition, the comment stated that

a review of the company's adverse experience files showed no

cardiovascular side effects from oxymetazoline that were not associated

with significant overuse (either in frequency of use, quantity of use,

or both). The comment added that a tabulation of the company's and

FDA's adverse reaction files for oxymetazoline for the period 1975 to

1989 showed only three cases of adverse reactions in children. The

comment stated that the scarcity of adverse reaction experiences

demonstrates that there is no safety problem. Further, the comment

contended that limiting pediatric formulations (0.025 percent) of

oxymetazoline to professional labeling (excluding use from consumer

labeling) is inappropriate because an OTC drug must first be available

to consumers with proper labeling before professional labeling can

apply. The comment contended that the agency's justification for

placing 0.025 percent oxymetazoline in professional labeling, i.e.,

that there is a theoretical possibility of a young child swallowing

excessive amounts of a potent long-acting drug due to difficulty in

administering accurate dosages, is unfounded. The comment stated that

if this problem does exist, it would also be a problem with the shorter

acting topically applied nasal decongestant drug products because these

shorter acting drug products are administered more often. If this is

the case, according to the comment, then the shorter acting drug

products labeled for use in young children should be labeled with the

same age restrictions as proposed for oxymetazoline.

With respect to the agency's concern that it is difficult to

measure the correct dose in a small child and that the child may

receive an excessive dose by swallowing the administered medication (50

FR 2220 at 2230), the comment contended that drops are more easily

administered than sprays. The comment stated that drops are

sufficiently accurate to assure safe use in children and that, to the

best of its knowledge, all pediatric formulations (0.025 percent) of

oxymetazoline are marketed for use as drops, not sprays. The comment

noted, specifically, that the orifice of the dropper of its

oxymetazoline pediatric nasal drops drug product is controlled so that

it consistently delivers an average drop volume of

0.0280.008 mL. The comment argued that this additional

safety feature further assures the accuracy of the dose. The comment

concluded that it is extremely unlikely that a child could receive a

dose of oxymetazoline that would have a systemic effect, even if the

child inadvertently swallowed some of the drops.

The comment maintained that restricting pediatric use of

oxymetazoline to professional labeling will not ease the task of

measuring a correct dose, nor will it cause a young child to swallow

any less of a nasal solution than he/she otherwise would. The comment

contended that dosing concerns can be addressed by consumer labeling.

For example, instructions for use in children might include a provision

that if less than a full dose is delivered on the first try, no further

attempt to readminister the drug should be made. Additionally, an

alternative safeguard could be provided by restricting the amount of

drug that a dropper can deliver, i.e., a safety dropper can be designed

to deliver approximately 6 drops which corresponds to the labeled

maximum dose of 3 drops in each nostril under conditions of normal use.

The comment concluded that the agency should accept the Panel's

recommendation to permit consumer labeling for oxymetazoline for

children 2 to under 6 years of age.

The agency has reviewed its adverse reaction reports for

oxymetazoline covering the period from 1969 to the present (Ref. 1).

Only five adverse reactions in children under 8 years of age have been

reported. Six adverse reactions involving xylometazoline in children

under 8 years of age have been reported to the agency since 1970 (Ref.

2). Except for a single death (without sufficient detail to attribute

cause in a 3-month-old male who presented a history consistent with

sudden infant death syndrome), all affected children recovered soon

after discontinuation of the medication. The reported reactions are

generally of expected events (i.e., excitation, agitation) or involve

concomitant medications associated with the reactions (e.g.,

antihistamines and sleepiness, or a previous history of rash from an

antibiotic). Considering the long marketing history and the extent of

the use of topical oxymetazoline and xylometazoline, the agency

considers the number and severity of the reported cases to be very low.

Biesalski and Marquart (Ref. 3) evaluated the nasal decongestant

effect of xylometazoline hydrochloride (0.1 and 0.01 percent) in 72

infants aged 5 days to 14 months, 3 premature infants, and 42 children.

An additional group of 48 infants was given xylometazoline in

concentrations ranging from 0.0005 to 0.005 percent. The investigators

measured blood pressure in 11 children and monitored cardiac activity

in 69 infants and found no effects caused by the drug. Four infants

with congenital heart defects had no side effects on the heart or

circulation from the drug. The investigators stated, ``No side effects

of any kind were noted, even in premature infants or in infants with

cardiac conditions.''

Based on this safety profile and the ability to control the amount

of drug administered per drop or spray, the agency concludes that

limiting information on the topical use of oxymetazoline and

xylometazoline in children 2 to under 6 years of age to professional

labeling only is unwarranted. This type of limitation would not

eliminate the dangers of misuse and overuse in this age group. The

agency agrees with the comment that the risk of overdose or misuse can

be adequately handled by the use of a dropper or spray that is designed

to restrict the amount of drug delivered to a maximum allowable dose

and by appropriate OTC labeling directions and warnings.

The United States Pharmacopeia discusses calibrated dropper

specifications where accuracy of dosage is important. The volume error

incurred in measuring any liquid by means of a calibrated dropper

should not exceed 15 percent under normal use conditions (Ref. 4). The

agency is incorporating this standard for a calibrated dropper in the

final monograph. The agency believes that this criterion will help

assure an accurate dose and minimize the risk of overdose.

To further emphasize to consumers the importance of proper

administration and the dangers of overdose in children in this age

group, the agency is incorporating the following statement in the

directions: ``Use only recommended amount.'' The agency recognizes that

the warnings for these two drugs already include the statement ``Do not

exceed recommended dosage.'' Nonetheless, the agency believes that an

additional statement in the directions sections will reinforce the

importance of not using an excessive amount of drug. The agency also

believes that the warning not to exceed the recommended doses within a

24-hour period will provide an additional safeguard against overdosing.

The agency is requiring that both of these statements appear in product

labeling in boldface type.

Accordingly, the agency is adding new sections for oxymetazoline

hydrochloride (Sec. 341.80(d)(2)(iv)(A)(2)) and xylometazoline

hydrochloride (Sec. 341.80(d)(2)(vii)(A)(2)). The agency is requiring

that pediatric products be marketed in a container with a controlled,

metered-dose children's safety dropper or spray that is calibrated to

deliver no more than a maximum allowable dose. Based on the information

on the controlled dropper provided by the comment, which is the

manufacturer of the major marketed OTC oxymetazoline pediatric nose

drop products, the following doses are being included in this final

monograph.

For oxymetazoline hydrochloride, the product must have either a

calibrated dropper or a metered-dose spray that delivers no more than

0.027 mg of oxymetazoline hydrochloride per three drops or three

sprays. The directions for use are to include the following

information: Children 2 to under 6 years of age (with adult

supervision): 2 or 3 drops or sprays in each nostril of a 0.025-percent

aqueous solution not more often than every 10 to 12 hours. Use only

recommended amount. Do not exceed 2 doses in any 24-hour period.

[previous two sentences in boldface type] Children under 2 years of

age: consult a doctor.

For xylometazoline hydrochloride, the product must have either a

calibrated dropper or metered-dose spray that delivers no more than

0.054 mg of xylometazoline hydrochloride per three drops or three

sprays. The directions for use are to include the following

information: Children 2 to under 6 years of age (with adult

supervision): 2 or 3 drops or sprays in each nostril of a 0.05-percent

aqueous solution not more often than every 8 to 10 hours. Use only

recommended amount. Do not exceed 3 doses in any 24-hour period.

[previous two sentences in boldface type] Children under 2 years of

age: consult a doctor.

Phenylephrine 0.125 percent aqueous solution is the only other OTC

topical nasal decongestant labeled for use by children 2 to under 6

years of age. The agency believes that products containing this drug

should also have a calibrated dropper or a metered-dose spray. Using

the same standard as above, the product must have either a calibrated

dropper or metered-dose spray that delivers no more than 0.135 mg per

three drops or three sprays. Similarly, the directions for use are to

include the following statement: ``Use only recommended amount.''

If manufacturers have information that demonstrates that an amount

of drug different than those listed above for three drops or sprays of

oxymetazoline hydrochloride, xylometazoline hydrochloride, and

phenylephrine hydrochloride, the agency will evaluate that information

and determine if the above standards should be changed. Manufacturers

should submit the information in a citizen petition in accord with

Sec. 10.30 (21 CFR 10.30).

References

(1) Department of Health and Human Services, Food and Drug

Administration, ``Spontaneous Reporting System, Line Listing of

Adverse Reports,'' 1969-1993.

(2) Department of Health and Human Services, Food and Drug

Administration, ``Spontaneous Reporting System, Line Listing of

Adverse Reports,'' 1970-1993.

(3) Biesalski, P., and K. Marquart, ``Therapeutic Aspects of

Rhinitis in Early Childhood, Thermoelectrode Investigations with

Nasal Decongestants'' (``Zur Behandlungder Rhinitis im fruhen

Kindesalter. Thermoelektrische Untersuchungen an abschwellenden

Nasenmittein'') (English Translation), Schweizerische Medizinische

Wochenschrift, 89(19):510-512, 1959.

(4) ``The United States Pharmacopeia XXII--The National Formulary

XVII,'' United States Pharmacopeial Convention, Inc., Rockville, MD,

p. 1684, 1989.

9. One comment requested that the status of phenylephrine

bitartrate be clarified in the final monograph. The comment stated that

data were submitted to the Cough-Cold Panel indicating that

phenylephrine bitartrate, while not as commonly used as the

hydrochloride salt of phenylephrine, had the same characteristics

(Refs. 1 and 2). The comment noted that the proposed dose of

phenylephrine hydrochloride in adults is 10 mg which is equivalent to

approximately 15.5 mg of phenylephrine bitartrate. Stating that the

noninclusion of phenylephrine bitartrate in the Cough-Cold Panel's

report and the tentative final monograph appeared to be an inadvertent

omission, the comment requested that phenylephrine bitartrate be

classified as a Category I oral nasal decongestant.

The agency acknowledges that phenylephrine bitartrate was submitted

as an oral nasal decongestant active ingredient in an effervescent

combination cold tablet for OTC use containing 7.8 mg phenylephrine

bitartrate (4.1 mg phenylephrine base) which is present in the same

amount in solution for oral use. The maximum recommended dose is 8

tablets in 24 hours. Therefore, the maximum dose of phenylephrine

bitartrate would be 62.4 mg (32.8 mg phenylephrine base) per day (Ref.

1). However, the ingredient apparently was not reviewed by the Cough-

Cold Panel or included in its report, or addressed in the tentative

final monograph for OTC nasal decongestant drug products. The agency

has reviewed the submitted data and notes that the submission (Ref. 1)

states that the Physicians' Desk Reference, 1972 edition, lists two

products containing phenylephrine bitartrate (Ref. 3). The agency has

determined that these two products are aerosol inhalation devices which

deliver micronized particles of isoproterenol hydrochloride and

phenylephrine bitartrate for inhalation by mouth into the bronchial

tree. The products have the following indications: (1) Acute bronchial

asthma and other allergic states, and (2) chronic obstructive pulmonary

diseases such as chronic bronchitis and pulmonary emphysema (Ref. 3).

The submission also includes an acute oral toxicity study conducted

on phenylephrine bitartrate, chlorpheniramine maleate, and

phenylephrine hydrochloride as individual active ingredients. The acute

oral LD50 for phenylephrine bitartrate alone is presented as 170.7

17.0 mg per kilogram (kg); that for phenylephrine

hydrochloride alone is presented as 61.3 11.6 mg/kg (Refs.

1 and 2). In addition, the submission includes a bioavailability (blood

level) study of phenylephrine bitartrate combined in an effervescent

cold tablet with aspirin and chlorpheniramine maleate (Ref. 2). The

study compares phenylephrine plasma levels obtained for three

combination drug products containing the following active ingredients:

(1) Aspirin, phenylephrine bitartrate (7.1 mg), and chlorpheniramine

maleate, (2) aspirin, phenylephrine hydrochloride (5 mg), phenindamine

tartrate, and caffeine, and (3) phenylephrine hydrochloride (20 mg) and

chlorpheniramine maleate. Although comparable plasma levels of

phenylephrine were obtained with the first and second test

formulations, the agency has determined that these bioavailability

studies do not demonstrate effectiveness because the claimed

pharmacological effectiveness of OTC drug monograph active ingredients

must be established by controlled clinical investigations (21 CFR

330.10(a)(4)(ii)). No clinical data were submitted to show the

effectiveness of phenylephrine bitartrate as an oral nasal

decongestant. Moreover, the agency has conducted an extensive

literature search and is unaware of any data or information in the

scientific literature regarding the use of phenylephrine bitartrate as

an oral nasal decongestant active ingredient. The products containing

phenylephrine bitartrate that were cited by the comment (Refs. 1 and 3)

are aerosol products administered by inhalation and are not indicated

for nasal decongestant use. Further, the submitted product has been

reformulated and no longer contains phenylephrine bitartrate (Ref. 4).

The agency concludes that the data are inadequate to generally

recognize phenylephrine bitartrate as safe and effective as an oral

nasal decongestant, and this ingredient is not being included in the

final monograph for OTC nasal decongestant drug products.

References

(1) OTC Vol. 040192.

(2) OTC Vol. 040193.

(3) ``Physicians' Desk Reference--1972,'' 26th ed., Medical

Economics, Inc., Oradell, NJ, pp. 1102 and 1105, 1972.

(4) Letter from B.S. Shuster, Miles Laboratories, Inc., to G.

Kerner, FDA, dated April 24, 1987, in OTC Vol. 04NFM, Docket No.

76N-052N, Dockets Management Branch.

10. One comment requested that a product containing phenol 1.56

percent, thymol, sodium perborate, methyl salicylate, alum powder,

sage, and honey, used as a spray, atomizer, swab, or gargle, be

considered in the nasal decongestant drug products rulemaking. The

labeling claim for the product is for ``hygienic care of * * * nasal

passages'' (Ref. 1). In a followup communication with the agency, the

comment clarified that phenol is the only active ingredient in the

product (Ref. 2).

No data on the use of 1.5 percent phenol for ``hygienic care of

nasal passages'' were submitted to the Cough-Cold Panel following the

``call-for-data'' notice that was published in the Federal Register of

August 9, 1972 (37 FR 16029), requesting data on any active ingredients

in OTC cold, cough, allergy, bronchodilator, and antiasthmatic drug

products. Nor were any data on phenol for this use submitted to the

agency for inclusion in the tentative final monograph for OTC nasal

decongestant drug products published in the Federal Register of January

15, 1985 (50 FR 2220). Thus, neither the Cough-Cold Panel in its report

(41 FR 38312), nor the agency in its tentative final monograph,

considered this ingredient or claim for topically applied nasal drugs

in the rulemaking for OTC nasal decongestant drug products. The comment

did not submit any data to demonstrate the safety and effectiveness of

the claimed active ingredient, phenol, in the nasal passages or to

substantiate the claim it requested for this ingredient. Nevertheless,

the agency has evaluated the claim ``hygienic care of nasal passages''

and considers this claim to be vague and meaningless because it does

not describe any therapeutic benefits to be obtained from use of the

product. Thus, the agency concludes that phenol as an active ingredient

and labeling for its use ``for hygienic care of nasal passages'' are

nonmonograph conditions.

References

(1) OTC Vol. 160233.

(2) Telephone communications between A. Horn, co-owner of marketing

rights for Formula U, and M. Benson, FDA, March 21 and March 30,

1984, in OTC Vol. 04NFM, Docket No. 76N-052N, Dockets Management

Branch.

D. Comments on Dosages for OTC Nasal Decongestant Active Ingredients

11. In response to the agency's proposal (50 FR 2220 at 2229 to

2230) that pseudoephedrine preparations be available at dosage levels

twice those previously permitted for OTC use, i.e., 60 mg instead of 30

mg, one comment expressed a hope that pseudoephedrine would continue to

be available in 30 mg tablet strength, or if in 60 mg strength, that

tablets will be scored for breaking.

The final monograph does not address tablet characteristics such as

shape, size, scoring, etc. However, manufacturers must provide

consumers with dosage forms and strengths that are consistent with the

dosages and directions for use in OTC drug monographs. The adult dosage

for products containing pseudoephedrine is 60 mg every 4 to 6 hours.

Manufacturers may market a 60-mg product with a one-tablet dosage or a

30-mg product with a two-tablet dosage. The pseudoephedrine dosage for

children 6 to under 12 years of age is 30 mg every 4 to 6 hours. Thus,

it is reasonable to expect that 30 mg tablets of pseudoephedrine will

continue to be available.

12. Several comments recommended that the agency consider new

weight-based/age-related pediatric dosing schedules for cough-cold drug

products (including nasal decongestants) based on a pediatric dosing

unit (PDU) concept that provides for additional age groupings developed

to better meet the needs of the growing pediatric patient. Some

comments suggested that the Cough-Cold Panel's recommended pediatric

dosing schedule of 6 to under 12 years and 2 to under 6 years be

replaced with the PDU concept that would utilize a pediatric dosage

schedule equivalent to 1/8 the adult dose and include additional age

breaks (i.e., 2-3, 4-5, 6-8, 9-10, and 11 years) and/or weight

groupings (i.e., 24-35, 36-47, 48-59, 60-71, and 72-95 pounds). Other

comments also recommended that this new pediatric dosing schedule be

optional. For products targeted primarily for adults, which also

incorporate some dosage recommendations for pediatric use, the comments

felt that it was reasonable to continue to use the dosing schedule

proposed in the tentative final monograph. But for products primarily

intended for pediatric use, the comments felt that there was a need for

incremental dosing throughout the entire pediatric (under 12 years) age

range consistent with the incremental age and weight ranges within the

typical growth patterns in children. Stating that the pediatric dosage

of cough-cold drug products should be reconciled with the dosage

schedules recommended by the Advisory Review Panel on OTC Internal

Analgesic and Antirheumatic Drug Products (Internal Analgesic Panel)

(42 FR 35346 at 35489 to 35491, July 8, 1977, which includes additional

age groupings), two comments contended that such a change would provide

consistency between the various monographs and allow for consistency in

the formulation of combination drug products containing a nasal

decongestant and an analgesic-antipyretic.

Two comments also recommended that the agency add a professional

dosing schedule for children under 2 years of age, based on the PDU

concept. As an example, one comment suggested that the professional

labeling section for oral pseudoephedrine be amended to include the

following: Children 1 year of age, 11.25 mg every 4 to 6 hours, not to

exceed 45 mg in 24 hours; children 4 months to under 1 year, 7.5 mg

every 4 to 6 hours, not to exceed 30 mg in 24 hours.

Because a number of OTC drug rulemakings could be affected if

pediatric dosages are revised as requested by the comments, the agency

has published a separate document in the Federal Register that

discusses pediatric dosages for OTC drug products. Therefore, comments

regarding a weight-based, age-related pediatric dosage schedule for

pseudoephedrine and other oral nasal decongestants are being deferred

at this time and have been addressed in a separate notice entitled

``Pediatric Dosing Information for OTC Human Drugs; Intent and Request

for Information,'' published in the Federal Register on June 20, 1988

(53 FR 23180). Should pediatric dosage schedules, in general, be

revised in the future, the final monograph for OTC nasal decongestant

drug products will be amended accordingly.

E. Comments on Labeling of OTC Nasal Decongestant Drug Products

13. Two comments stated that FDA lacks statutory authority to

prescribe exclusive lists of terms from which indications for use for

OTC drug products must be drawn and to prohibit alternative labeling

terminology which is truthful, accurate, not misleading, and

intelligible to the consumer. One comment recommended that, instead of

prohibiting the use of alternative truthful terminology, FDA should

permit manufacturers to choose consumer oriented language to

communicate the desired label indications, so long as such language is

not false or misleading. Both comments noted that FDA had proposed

certain revisions to the ``Exclusivity Policy'' on April 22, 1985 (50

FR 15810) and stated that they would be submitting further comments on

that proposal.

In the Federal Register of May 1, 1986 (51 FR 16258), the agency

published a final rule changing its labeling policy for stating the

indications for use of OTC drug products. Under 21 CFR 330.1(c)(2), the

label and labeling of OTC drug products are required to contain in a

prominent and conspicuous location, either: (1) The specific wording on

indications for use established under an OTC drug monograph, which may

appear within a boxed area designated ``approved uses''; (2) other

wording describing such indications for use that meets the statutory

prohibitions against false or misleading labeling, which shall neither

appear within a boxed area nor be designated ``approved uses''; or (3)

the approved monograph language on indications, which may appear within

a boxed area designated ``approved uses,'' plus alternative language

describing indications for use that is not false or misleading, which

shall appear elsewhere in the labeling. All OTC drug labeling required

by a monograph or other regulation (e.g., statement of identity,

warnings, and directions) must appear in the specific wording

established under the OTC drug monograph or other regulation where

exact language has been established and identified by quotation marks,

e.g., 21 CFR 201.63 or 330.1(g).

In the tentative final monograph for OTC nasal decongestant drug

products (50 FR 2220 at 2238), supplemental language relating to

indications had been proposed and captioned as ``Other allowable

indications.'' Under FDA's revised labeling policy (51 FR 16258), such

statements are included at the tentative final stage as examples of

other truthful and nonmisleading language that would be allowed

elsewhere in the labeling. In accordance with the revised labeling

policy, such statements would not be included in a final monograph.

However, the agency has decided that, because these additional terms

have been reviewed by FDA, they should be incorporated, wherever

possible, in final OTC drug monographs under the heading

``Indications'' as part of the indications developed under that

monograph. (See comment 16 in section I.E. of this document.)

14. Four comments requested that Sec. 341.80(b) of the tentative

final monograph be amended to allow manufacturers to choose from among

any of three basic indications provided, i.e., the common cold (cold),

allergy, or sinusitis. The comments contended that the intended target

populations for products promoted and marketed for treating the common

cold, allergy, and sinusitis are different and that specific products

should be allowed to be designed or positioned for specific consumer

populations. One comment pointed out that the use of all three

indications for all products containing oral nasal decongestants, as

proposed in Sec. 341.80(b), may not only be extraneous, but potentially

confusing to consumers. Two comments provided examples of how this

labeling could be extraneous: (1) Indications for hay fever or allergic

rhinitis would be inappropriate on a product marketed as a ``cold''

product, and (2) indications for a cold would be inappropriate for

persons suffering from allergy or sinusitis. One comment added that

small packages of multi-ingredient combination products contain little

label space for necessary indications and warnings. It is therefore

important for the distributor of a product to have the option to

eliminate indications which are not applicable to a particular segment

of the market for which the product is positioned.

The comments requested, therefore, that the indications in

Sec. 341.80(b) be amended to allow manufacturers to choose from among

any of the basic indications (i.e., the common cold (cold), allergy, or

sinusitis) that are appropriate for the consumer market segment to

which the product is directed. One comment suggested that

Sec. 341.80(b)(1) be modified to read as follows:

The labeling of the product contains a statement of the

indications under the heading ``Indications'' which includes one or

more of the following indications: ``For the temporary relief of

nasal congestion due to'' (select one of the following) ``the common

cold (cold),'' ``hay fever (allergic rhinitis),'' or ``associated

with sinusitis.''

The agency agrees with the comments that manufacturers should be

allowed to choose from among any of the indications proposed for nasal

decongestant drug products in Sec. 341.80(b)(1) that are consistent

with the intended use of the product.

Thus, in this final monograph the agency is revising the

``Indications'' in Sec. 341.80(b)(1), to read as follows: (Select one

of the following: ``For the temporary relief of nasal congestion'' or

``Temporarily relieves nasal congestion'') (which may be followed by

any of the following in (i), (ii), and (iii) below):

(i) ``due to'' (select one of the following: ``the common cold'' or

``a cold'').

(ii) ``due to'' (select one of the following: ``hay fever,'' ``hay

fever (allergic rhinitis),'' ``hay fever or other upper respiratory

allergies,'' or ``hay fever or other upper respiratory allergies

(allergic rhinitis)'').

(iii) ``associated with sinusitis.''

15. With regard to the indications proposed in Sec. 341.80(b), two

comments stated that the phrases ``for the temporary relief of'' and

``temporarily relieves'' are similar and should be interchangeable.

The agency agrees with the comments that the phrases are

interchangeable. Therefore, the agency has included the option of using

either phrase in the indications included in Sec. 341.80(b) of this

final monograph. (See comments 14 and 16 in section I.E. of this

document.)

16. One comment requested that the ``other allowable indications''

proposed in Sec. 341.80(b)(2) of the tentative final monograph be

alternative statements rather than additional statements to the

indications proposed in Sec. 341.80(b)(1). The comment contended that

this would permit meaningful alternate ``consumer oriented'' label

indications. Another comment assumed that the ``other allowable

indications'' proposed in Sec. 341.80(b)(2) may be identified on

product labels as ``other indications'' if they are separate from the

indications identified in Sec. 341.80(b)(1) and are not given greater

prominence.

In this final monograph, the agency is revising the indications in

Sec. 341.80(b)(1) to allow manufacturers the option of using one or

more of the indications (see comment 14 in section I.E. of this

document.) The agency considers the required indication statement(s)

essential in providing adequate and informative labeling to the

consumer. Under the agency's revised labeling policy for OTC drug

products, discussed in comment 13 in section I.E. of this document, the

``other allowable indications'' that were proposed in Sec. 341.80(b)(2)

of the tentative final monograph have been included in the final

monograph as part of the indications in Sec. 341.80(b). However, the

agency does not consider the text of these ``other allowable''

indication statements as providing complete information that is

comparable to the information contained in Sec. 341.80(b)(1). Because

they provide additional, complementary information, the previous

``other allowable'' indications are included in Sec. 341.80(b)(2) of

the final monograph as statements that may appear in the ``APPROVED

USES'' boxed area in the labeling, in addition to one or more of the

indications in Sec. 341.80(b)(1).

Therefore, the labeling of the product may contain any (one or

more) of the following statements, which appear in Sec. 341.80(b)(2) of

this final monograph, provided the required information identified in

Sec. 341.80(b)(1) (see comment 14 in section I.E. of this document) is

also included:

(i) (Select one of the following: ``For the temporary relief of''

or ``Temporarily relieves'') (select one of the following: ``stuffy

nose,'' ``stopped up nose,'' ``nasal stuffiness,'' or ``clogged up

nose.'')

(ii) (Select one of the following: ``Reduces swelling of,''

``Decongests,'' or ``Helps clear'') ``nasal passages; shrinks swollen

membranes.''

(iii) ``Temporarily restores freer breathing through the nose.''

(iv) ``Helps decongest sinus openings and passages; temporarily

relieves sinus congestion and pressure.''

(v) ``Promotes nasal and/or sinus drainage; temporarily relieves

sinus congestion and pressure.''

(See also comment 17 in section I.E. of this document.)

17. One comment requested modification of the ``other allowable

indications'' for nasal decongestant drug products in proposed

Sec. 341.80(b)(2)(i) to include the terms ``stuffed-up head'' and

``stuffy head'' as follows: ``For the temporary relief of (select one

of the following): stuffy nose, stopped-up nose, nasal stuffiness,

clogged-up nose, stuffed-up head, stuffy head.''

The agency does not consider the terms ``stuffed-up head'' and

``stuffy head'' specific enough to be included in this final monograph.

The agency believes that other terms could be used in the indication

statements to provide more specific information to consumers about the

action of this type of drug product than the comment's suggestion of

the general terms ``stuffed up head'' and ``stuffy head.'' In the

tentative final monograph, the agency included ``relieves sinus

pressure'' as a Category I indication for nasal decongestants (50 FR

2220 at 2231). Sinus pressure and sinus congestion are closely

associated and if congestion is relieved, pressure also would be

relieved (50 FR 2220 at 2232). Therefore, in this final monograph, the

agency is including the term ``sinus congestion'' in the indications in

Sec. 341.80(b)(2)(iv) and (b)(2)(v). The agency concludes that the

terms ``sinus congestion'' and ``sinus pressure'' provide more specific

information than the comment's suggested terms. In addition, the agency

is including these terms in Sec. 341.80(b)(2)(iv) and (b)(2)(v) because

those paragraphs primarily deal with ``sinus'' conditions, whereas the

indication in Sec. 341.80(b)(2)(i) primarily deals with ``nose''

conditions. (See comment 16 in section I.E. of this document for

additional discussion of the other indications included in this final

monograph.)

However, as discussed in comment 13 in section I.E. of this

document, the agency has revised its labeling policy for OTC drug

products. FDA has found that it simply is not practical--in terms of

time, resources, and other considerations--to set standards for all

labeling found in OTC drug products. Accordingly, OTC drug monographs

directly address only those labeling items that are related in a

significant way to the safe and effective use of covered products by

lay persons. These labeling items are the product statement of

identity; names of active ingredients; indications for use; directions

for use; warnings against unsafe use, side effects, and adverse

reactions; and claims concerning mechanism of drug action. Truthful and

nonmisleading terms that provide additional information about an OTC

drug product but are not directly related to its safe and effective use

are considered outside the scope of the OTC drug review and may appear

elsewhere in the labeling, separate from the monograph approved

statements. Thus, because consumers are familiar with and use terms

such as ``stuffed-up head'' and ``stuffy head,'' the agency considers

these terms as acceptable to be included elsewhere in the labeling (but

such terms may not be intermixed with any portion of the labeling

required by the monograph and may not detract from such required

information). Terms outside the scope of the review will be evaluated

by the agency on a product-by-product basis, under the provision of

section 502 of the act relating to labeling that is false or

misleading.

18. One comment requested that the indication, ``helps (select one

of the following: relieve, alleviate, decrease, reduce) post-nasal

drip'' be added as an additional consumer claim for nasal decongestant

drug products.

The Cough-Cold Panel placed a similar claim, ``checking post-nasal

drip,'' in Category III because such claims are unsubstantiated for

nasal decongestants unless studies specifically designed to assess

``post-nasal drip'' are presented. The Cough-Cold Panel stated in 41 FR

38415 that studies of nasal decongestants have assessed the effect of

nasal airway resistance or the ease of breathing but not the effect on

rhinorrhea that causes post-nasal drip. The comment did not submit any

data concerning the effect of nasal decongestants on rhinorrhea that

would support a claim for ``post-nasal drip.''

Further, the agency is unaware of any data to support consumer

recognition of an indication regarding post-nasal drip. The agency

reviewed information submitted to the antihistamine final monograph

rulemaking requesting an indication for ``post- nasal drip.'' The

comment asserted that substantial numbers of consumers recognize that

relief of ``post-nasal drip'' is a desirable end benefit and that

consumers clearly understand the term ``post-nasal drip.'' The comment

provided two consumer mail panel studies, which were designed to

investigate consumer attitudes towards, and usage of, sinus and hay

fever remedies. The comment stated that of the 263 responding sinus

sufferers, 49 percent (129) considered relief of post-nasal drip

important when choosing a sinus remedy. Similarly, 48 percent (119) of

the 248 hay fever respondents indicated that relief of post nasal drip

was important when choosing a hay fever product. The agency's review of

the studies disclosed that they were not designed to demonstrate the

effectiveness of OTC antihistamine drug products in relieving the

symptom ``post-nasal drip'' or provide a basis for a ``post-nasal

drip'' indication. These data, therefore, are not useful in supporting

a ``post-nasal drip'' indication for nasal decongestant or

antihistamine drug products.

Clinical studies specifically designed to demonstrate the

effectiveness of nasal decongestants in relieving ``post-nasal drip''

would be necessary before this claim could be used in the labeling of

any nasal decongestant drug product. Such studies should be designed to

evaluate the symptom of ``post-nasal drip'' in terms of specific

symptoms that can be recognized by consumers as ``post-nasal drip.''

The agency suggests that any party interested in studying the use of a

nasal decongestant for this claim meet with the agency to discuss an

appropriate protocol before beginning the study. For the above reasons,

indications pertaining to ``post-nasal drip'' are not being included in

this final monograph for OTC nasal decongestant drug products.

19. Two comments stated that the agency should differentiate

between ``Warnings'' and ``Cautions'' in OTC drug labeling, and one

comment objected to the proposed elimination of the term ``Caution(s)''

in the labeling of OTC drug products. The comments contended that

``Warnings'' are harsher (stronger) and more serious than ``Cautions''

and even preclude use of a product under certain conditions. One

comment stated that a ``Caution,'' on the other hand, does not preclude

use unless something occurs during use, but it often alerts the

consumer to a potential problem. The comment added that a caution may

also address a monitoring function to be performed while the product is

in use. The second comment stated that a caution should be used to

convey important information related to the safe and effective use of

the product, but allow for judgment on the part of the user, e.g.,

``This product may cause drowsiness.'' The comment felt that the

importance of the ``Warnings'' section was undermined if it contains

too much information or if it includes less than serious language. The

comment provided several examples of the differences between warnings

and cautions and suggested that the agency also consider the term

``precautions.''

Section 502(f)(2) of the act states, in part, that any drug

marketed OTC must bear in labeling ``* * * such adequate warnings * * *

as are necessary for the protection of users * * *.'' Section

330.10(a)(4)(v) of the OTC drug regulations provides that labeling of

OTC drug products should include ``* * * warnings against unsafe use,

side effects, and adverse reactions * * *.''

The agency notes that historically there has not been consistent

usage of the signal words ``warning'' and ``caution'' in OTC drug

labeling. For example, in Secs. 369.20 and 369.21 (21 CFR 369.20 and

369.21), which list ``warning'' and ``caution'' statements for drugs,

the signal words ``warning'' and ``caution'' are both used. In some

instances, either of these signal words is used to convey the same or

similar precautionary information. In addition, the term

``precaution(s),'' as in ``Drug Interaction Precaution(s)'' is often

used in OTC drug monographs, but is listed under ``Warnings'' as, for

example, in the rulemakings for OTC nasal decongestant drug products

and OTC bronchodilator drug products. (See the Federal Register of

January 15, 1985 (50 FR 2220 at 2239) and October 2, 1986 (51 FR 35326

at 35339), respectively.)

FDA has considered which of these signal words would be most likely

to attract consumers' attention to that information describing

conditions under which the drug product should not be used or its use

should be discontinued. The agency concludes that the signal word

``warning'' is more likely to flag potential dangers so that consumers

will read the information being conveyed. The agency is not convinced

that consumers will make the distinctions between ``warnings'' and

``cautions'' that the comments have made. Further, the agency does not

believe that the importance of the ``Warnings'' section will be

undermined if all of the information about unsafe use, side effects,

and adverse reactions is presented under a single heading. Therefore,

FDA has determined that the signal word ``warning,'' rather than the

word ``caution,'' will be used routinely in OTC drug labeling that is

intended to alert consumers to potential safety problems. However,

except in instances where the agency has stated that a particular

warning statement must appear as the first warning after the

``Warnings'' heading, the agency has no objections if manufacturers

list the various warnings statements in their order of preference,

e.g., listing first those they consider more serious followed by those

they consider to be less serious statements. Drug interaction

precaution information will continue to be listed under the heading

``Drug Interaction Precautions'' as part of the warnings information.

20. One comment stated that it is difficult to read labels of nasal

decongestant drug products because the containers are small and the

print on the labels also is small. The comment was particularly

concerned that the required warnings would not be legible and

recommended that the warnings should be ``clearly, in sizable print, be

evident, but only a minimum amount.'' The comment stated that it would

be more useful if ``warning sheets'' or booklets were available with

nasal decongestant packages. A second comment requested larger print

size and more prominent location of warnings on nasal decongestant

products.

In the tentative final monograph for OTC nasal decongestant drug

products (50 FR 2220), the agency simplified or revised several and

deleted some of the warnings recommended by the Cough-Cold Panel. (See

comments 13, 21, 24, 26, 28, and 29 in the tentative final monograph.)

The agency believes that the labeling proposed in this final monograph

includes only essential information that is necessary to assure proper

and safe use of OTC nasal decongestant drug products by consumers.

Moreover, the labeling of drugs must comply with section 502(c) of the

act which states that a drug shall be deemed to be misbranded:

If any word, statement, or other information required by or

under authority of this Act to appear on the label or labeling is

not prominently placed thereon with such conspicuousness (as

compared with other words, statements, designs, or devices, in the

labeling) and in such terms as to render it likely to be read and

understood by the ordinary individual under customary conditions of

purchase and use.

In general, a product container label needs to bear the following

information: A statement of ingredients (section 502(e) of the act),

name and address of the manufacturer, repacker, or distributor (section

502(b)(1) of the act), a net contents statement (section 502(b)(2) of

the act), a lot number (21 CFR 201.18), and an expiration date (21 CFR

201.17). In some situations, other labeling information is required to

appear on the immediate container labeling, e.g., the Reye syndrome

warning for drug products containing salicylates (21 CFR 201.314).

When an OTC drug product is packaged in a container that is too

small to contain all the required labeling, the agency recommends that

the product be enclosed in a carton or be accompanied by a package

insert or booklet that contains the information complying with the

monograph. Manufacturers are also encouraged to print a statement on

the product container label, carton, or package insert suggesting that

the consumer retain the carton or package insert for complete

information about the use of the product when all the required labeling

does not appear on the product container label. Manufacturers who use

supplemental labeling should be able to readily provide all labeling

information in a larger print size than if all of the labeling is

presented on the immediate container. Further, the agency is aware that

many manufacturers use bold lettering and a colored label to emphasize

certain labeling information, including warnings, on the immediate

container and in package inserts. All manufacturers are encouraged to

use these as appropriate to highlight and emphasize certain labeling

information for the consumers. The agency previously published a

request for public comment (56 FR 9363 to 9365, March 6, 1991) on the

issue of print size and style of labeling for OTC drug products, and

will evaluate comments received before making a final decision on the

feasibility of establishing a Federal regulation pertaining to print

size and style of OTC labeling.

The Nonprescription Drug Manufacturers Association (NDMA) has

recently promulgated guidelines for industry to consider when examining

product labels for readability and legibility (Ref. 1). These

guidelines are designed to assist manufacturers in making the labels of

OTC drug products as legible as possible. The agency commends this

voluntary effort and urges all OTC drug manufacturers to examine their

product labels for legibility.

Reference

(1) ``Label Readability Guidelines,'' The Nonprescription Drug

Manufacturers Association, Washington, copy included in OTC Vol.

04NFM, Docket No. 76N-052N, Dockets Management Branch.

21. Two comments pointed out that the warning for oral nasal

decongestants in proposed Sec. 341.80(c)(1)(i)(b) (which states: ``Do

not take this product for more than 7 days. If symptoms do not improve

or are accompanied by fever, consult a doctor.'') and a similar warning

for children in Sec. 341.80(c)(1)(ii)(b), could be read to warn against

the use of Category I OTC oral nasal decongestant drug products without

first consulting a doctor if a fever is present initially. The comments

stated that in the advance notice of proposed rulemaking for OTC

internal analgesic-antipyretic drug products, the Internal Analgesic

Panel classified as Category I the combinations of one or two Category

I analgesic-antipyretic active ingredients ``* * * with generally

recognized as safe and effective nasal decongestant active

ingredient(s) provided the product is labeled for the concurrent

symptoms involved, * * * for the reduction of fever, * * * `` (42 FR

35370, July 8, 1977). One comment contended that while the proposed

warning may have limited significance for single ingredient nasal

decongestant drug products, it would have a serious and unwarranted

adverse effect on the use of combination drug products containing a

nasal decongestant along with an analgesic-antipyretic. The comment

urged that the proposed warning be reworded to explicitly permit use of

a combination product containing an oral nasal decongestant and an

antipyretic agent(s) when concurrent symptoms of nasal congestion and

fever are present.

The second comment stated that billions of doses of oral nasal

decongestants have been used OTC for many years without such a label

warning. The comment added that it was unaware of any safety problems

that have occurred as a direct consequence of a consumer using a nasal

decongestant in the presence of minor fever of short duration, which is

the case in the vast majority of instances in which fever is present.

On the other hand, the comment contended, the presence of high fever is

of importance to the well-being of the consumer, and a doctor should be

consulted if such occurs. The comment requested that the above-

referenced warnings be amended to read: ``(b) If symptoms do not

improve in 7 days or are accompanied by high fever, consult a doctor.''

The comment also stated that some allergic episodes (and even

colds) occasionally continue for more than 7 days, particularly in

humid climates or in periods of high pollen counts. Therefore, an

absolute 7-day use limitation may not always be appropriate. Moreover,

the comment stated that its amended warning would be equally

informative to consumers who may be taking an oral nasal decongestant

product without an antipyretic ingredient as well as to those who may

take a combination which includes antipyretic ingredient(s). Thus, the

comment requested that this amended warning be included in the

following final monographs: (1) OTC nasal decongestant drug products;

(2) OTC internal analgesic-antipyretic drug products; and (3) OTC

cough-cold combination drug products.

The Cough-Cold Panel noted that a slight fever may be present with

the common cold (41 FR 38312 at 38321). The Internal Analgesic Panel

stated that antipyretics (fever reducers) may be safely used for self-

medication when fever is due to the common cold or flu (42 FR 35346 at

35351). The warnings in Sec. 341.80(c)(1)(i)(b) and (c)(1)(ii)(b) are

not meant to restrict use of an oral nasal decongestant in the presence

of minor fever of short duration such as that which might be associated

with a common cold. The agency agrees that a nasal decongestant can be

used in such situations. The intent of the warnings is to alert

consumers that the presence of a fever might indicate a more serious

condition, such as a secondary bacterial infection, for which a doctor

should be consulted. For example, a nasal obstruction accompanying a

common cold can result in a middle ear infection (acute otitis media).

Usually, the first complaint of a middle ear infection is a persistent,

severe earache. Other symptoms, such as fever, nausea, vomiting, and

diarrhea may occur in young children (Ref. 1). Pneumonia is also often

preceded by an upper respiratory infection. Symptoms include chills,

sharp pain in the chest, cough, fever, and headache (Ref. 2). Thus,

because the agency believes that it is important for consumers to

recognize that all fevers are not insignificant occurrences, the word

``fever'' as proposed in the tentative final monograph is being

retained in this final monograph.

This warning for oral nasal decongestant drug products is

consistent with the warning included in the final monographs for single

ingredient antitussive drug products and single ingredient expectorant

drug products, which states: ``* * * If cough persists for more than 1

week, tends to recur, or is accompanied by fever, rash, or persistent

headache, consult a doctor.'' (See Secs. 341.74(c)(1) and

341.78(c)(2)). These warnings are not meant to restrict the use of an

antitussive or an expectorant in the presence of minor fever of short

duration such as that which might be associated with a common cold.

However, as with the warning for nasal decongestants, the intent of the

warnings is to alert consumers that the presence of a fever might

indicate a more serious condition, and a doctor should be consulted.

The agency has previously considered inclusion of the word ``high''

(in reference to fever) in this warning in the final monograph for OTC

antitussive drug products. (See 52 FR 30042 at 30054, August 12, 1987.)

In that proceeding, the agency determined that the word ``high'' would

not be included in the warning because it is important for the consumer

to recognize the presence of fever regardless of whether the fever is

high or low. The agency concludes that this principle is equally

applicable to the labeling of OTC nasal decongestant drug products.

Therefore, the agency is not adopting the second comment's suggested

wording related to the use of the term ``high'' to describe fever.

The agency agrees with the comment that an absolute 7-day

limitation may not always be appropriate for oral nasal decongestant

drug products. Further, the final monographs for OTC antitussive and

expectorant drug products (21 CFR part 341) do not impose a 7-day use

limitation, and the agency concludes that such a limitation is also not

necessary for oral nasal decongestant drug products. Therefore, the

warnings proposed in Sec. 341.80(c)(1)(i)(b) and (c)(1)(ii)(b) in the

tentative final monograph are revised as follows: ``If symptoms do not

improve within 7 days or are accompanied by fever, consult a doctor.''

These warnings appear in Sec. 341.80(c)(1)(i)(B) and (c)(1)(ii)(B) of

this final monograph.

With regard to labeling of cough-cold combination drug products for

which the labeling in the individual applicable monographs conflicts or

is inappropriate, the agency has proposed specific labeling in

Sec. 341.85 of the tentative final monograph for OTC cough-cold

combination drug products. (See 53 FR 30522 at 30562 to 30564.) The

antipyretic ingredient in an oral nasal decongestant-analgesic-

antipyretic combination drug product would be used specifically to

treat a fever. Normally, the labeling for such a product would contain

the appropriate portions of the monograph labeling for nasal

decongestant and analgesic- antipyretic ingredients. However, the

agency recognized that the warnings for nasal decongestants proposed in

Sec. 341.80(c)(1)(i)(b) and (c)(1)(ii)(b) of the tentative final

monograph would be inconsistent with the presence of the analgesic-

antipyretic ingredient(s) in the product. Therefore, to eliminate this

inconsistency, the agency proposed the following warning for such

products labeled for use by adults in the cough-cold combinations

tentative final monograph: ``Do not take this product for more than 10

days. If symptoms do not improve or are accompanied by fever that lasts

for more than 3 days, or if new symptoms occur, consult a doctor.'' For

products labeled for use by children 2 to under 12 years of age, the

proposed warning reads as follows: ``Do not give this product to

children for more than 5 days. If symptoms do not improve or are

accompanied by fever that lasts for more than 3 days, or if new

symptoms occur, consult a doctor.'' (See 53 FR 30522 at 30563.) The

agency will address this warning in the final monograph for OTC cough-

cold combination drug products, in a future issue of the Federal

Register.

References

(1) Berkow, R., editor, ``The Merck Manual,'' 16th ed., Merck

and Co., Rahway, NJ, pp. 2331-2332, 1992.

(2) Berkow, R., editor, ``The Merck Manual,'' 16th ed., Merck

and Co., Rahway, NJ, pp. 681-685, 1992.

22. One comment contended that the agency's proposed drug

interaction precautions for adults and children in

Sec. 341.80(c)(1)(i)(d) and Sec. 341.80(c)(1)(ii)(d), respectively,

essentially duplicate statements required in other warnings. The

comment requested that the proposed warning in Sec. 341.80(c)(1)(i)(c)

be modified to include the ``Drug Interaction Precaution'' information

in Sec. 341.80(c)(1)(i)(d) to read as follows: ``Do not take this

product if you are being treated for heart disease, depression, high

blood pressure, thyroid disease, diabetes, or have difficulty in

urination due to enlargement of the prostate gland unless directed by a

doctor.'' Likewise, the comment requested that the proposed warning in

Sec. 341.80(c)(1)(ii)(c) be modified to include the ``Drug Interaction

Precaution'' information in Sec. 341.80(c)(1)(ii)(d) to read: ``Do not

give this product to children who are being treated for heart disease,

thyroid disease, diabetes, high blood pressure, or depression unless

directed by a doctor.'' The comment concluded that these revisions

would eliminate redundancy in the warnings language.

The agency agrees that the statements are similar but does not

agree that drug interaction precautions should be combined with

warnings. The agency believes the drug interaction precaution needs to

be highlighted in order to adequately inform individuals who may not

otherwise be aware of serious (even life-threatening) adverse effects

due to potentiation of the adverse effects of one drug by another taken

concurrently.

In discussing drug interactions, the Cough-Cold Panel stated that

it had recommended appropriate labeling for drug interactions where

there are serious concerns (41 FR 38312 at 38335). In the case of nasal

decongestants, the Cough-Cold Panel stated that patients taking other

drugs (e.g., monoamine oxidase inhibitors whose action can intensify

sympathomimetic drug action), should not use oral nasal decongestants

except under the advice and supervision of a physician (41 FR 38312 at

38397). The Cough-Cold Panel therefore recommended a specific warning,

in the form of a drug interaction precaution, to alert the subgroup of

the OTC nasal decongestant target population taking prescription

medication for certain chronic disease conditions, to their special

risk in using OTC nasal decongestants concurrently. The Cough-Cold

Panel recommended the following drug interaction precaution statement:

``Do not take this product if you are presently taking a prescription

antihypertensive or antidepressant drug containing a monoamine oxidase

inhibitor except under the advice and supervision of a physician.''

(See 41 FR 38312 at 38423.) For these reasons, the agency also proposed

this drug interaction warning for OTC sympathomimetic amine

bronchodilator drugs (41 FR 38312 at 38370 through 38373).

The agency discussed this statement in the tentative final

monograph for OTC nasal decongestant drug products (50 FR 2220, January

15, 1985). In response to the Cough-Cold Panel's recommendation, two

comments contended that terms such as ``antihypertensive,''

``antidepressant,'' and ``monoamine oxidase inhibitor'' (MAOI) are

highly technical; that only a small percentage of the population is

likely to understand this warning; and that including such a warning in

the labeling of an OTC drug is contrary to the well-established

principle that unnecessary or confusing precautions tend to dilute the

significance of all instructions in the labeling and, hence, should be

avoided (50 FR 2220 at 2231). Accordingly, the agency proposed to

simplify the precaution statement as follows: ``Drug interaction

precaution. Do not take this product if you are presently taking a

prescription drug for high blood pressure or depression, without first

consulting your doctor.'' (See proposed Sec. 341.80(c)(1)(i)(d).) Also

with the tentative final monograph, the agency proposed to add new

Sec. 341.80(c)(1)(ii)(d) for children, as follows: ``Drug Interaction

Precaution: Do not give this product to a child who is taking a

prescription drug for high blood pressure or depression, without first

consulting the child's doctor.'' The wording for OTC bronchodilator

drug products was similarly revised in the tentative final monograph

(47 FR 47520 at 47523) and the final monograph (51 FR 35326 at 35338).

After publication of the tentative final monograph for OTC nasal

decongestant drug products, the agency became aware of a need to modify

the wording of the drug interaction precaution statement. Information

was submitted to the agency showing that the antitussive ingredient

dextromethorphan interacts with prescription drugs containing MAOI's.

Case reports and articles in the literature describe severe reactions,

including death, from this combination of drugs. In preparing a

proposal to amend the final monograph for OTC antitussive drug products

to provide for a new drug interaction precaution for that class of OTC

drugs, the agency determined a need to modify the language of the

existing precaution statement for OTC bronchodilator and nasal

decongestant drugs, largely because of expanded use of MAOI drugs.

There is evidence that MAOI drugs are also being used to treat

conditions, such as bulimia and panic disorder, that are not readily

associated with depression. Further, the newer MAO B inhibitors are

being used to treat Parkinson's disease. Finally, the use of MAOI's in

hypertension has essentially ceased. In order to have consistent

language among the three drug classes, the agency published proposals

to amend the antitussive final monograph (57 FR 27666), bronchodilator

final monograph (57 FR 27662), and the nasal decongestant tentative

final monograph (57 FR 27658) to provide for the following warning:

Drug interaction precaution. Do not use this product if you are

taking a prescription drug containing a monoamine oxidase inhibitor

(MAOI) (certain drugs for depression, psychiatric or emotional

conditions), without first consulting your doctor. If you are

uncertain whether your prescription drug contains an MAOI, consult

your doctor before taking this product.

The case reports and literature articles are discussed in detail in the

proposed amendment to the final monograph for OTC antitussive drug

products (57 FR 27666).

The comments received in response to the proposed amendments are

discussed in detail in a final rule for OTC antitussive drug products

(58 FR 54232, October 20, 1993) and OTC bronchodilator drug products

(58 FR 54238, October 20, 1993). In brief, four comments that suggested

modifications to the wording of the drug interaction precaution

statement were not adopted, and one comment that suggested a 2-week

washout period be included was adopted.

Accordingly, the agency is amending Sec. 341.80(c)(1)(i)(d) for OTC

nasal decongestant drug products to read:

Drug interaction precaution. Do not use this product if you are

now taking a prescription monoamine oxidase inhibitor (MAOI)

(certain drugs for depression, psychiatric or emotional conditions,

or Parkinson's disease), or for 2 weeks after stopping the MAOI

drug. If you are uncertain whether your prescription drug contains

an MAOI, consult a health professional before taking this product.

Also, the agency is amending Sec. 341.80(c)(1)(ii)(d) to read:

Drug interaction precaution. Do not give this product to a child

who is taking a prescription monoamine oxidase inhibitor (MAOI)

(certain drugs for depression, psychiatric or emotional conditions),

or for 2 weeks after stopping the MAOI drug. If you are uncertain

whether your child's prescription drug contains an MAOI, consult a

health professional before giving this product.

23. Three comments contended that the agency should not require the

warning for topical nasal decongestants proposed in

Sec. 341.80(c)(2)(iii)(b) of the tentative final monograph, which

reads: ``Do not use this product if you have heart disease, high blood

pressure, thyroid disease, diabetes, or difficulty in urination due to

enlargement of the prostate gland unless directed by a doctor.''

One comment contended that the warning should not be required

because systemic distribution of topical nasal decongestants is

minimal. A second comment stated that such a warning is not warranted

for topical products containing oxymetazoline. Referring to studies in

dogs that compared the doses of oxymetazoline given intranasally and

intravenously to elicit a cardiovascular effect (i.e., increase in

blood pressure) and that showed substantial differences, the comment

indicated that the amount of oxymetazoline required to elicit any

systemic effect by the intranasal route would be virtually unachievable

with marketed products. Based on the amount of the drug which is

required to cause a systemic effect, the comment argued that there is

no reason to believe that patients with cardiac problems, diabetes, or

hyperthyroidism would be at any greater risk than the general

population. In addition, the comment stated that its review of adverse

experience files showed no cardiovascular side effect from

oxymetazoline that was not associated with significant overuse, either

in frequency of use, quantity of use, or both. The comment stated that

the agency's proposed warning not to overuse the product deals

adequately with risks to patients with cardiac problems, diabetes, or

hyperthyroidism and that the additional warning is unnecessary.

The third comment indicated that the proposed warning should be

deleted from the monograph because it is conjectural that systemic

effects can occur as a result of absorption from the gastrointestinal

tract if an excessive amount of topically applied nasal decongestant

drug is swallowed. The comment stated that it was unaware of any data

that support the position that an excessive amount of drug can be, or

is, swallowed when the product is used as directed. The comment cited

numerous studies to support its position (Refs. 1 through 19). In

addition, the comment attached a summary of published studies

addressing the issue of intranasally-applied decongestants and possible

cardiovascular changes (Ref. 20). The summary indicated that oral

threshold doses reported to be associated with changes in pulse rate

and/or blood pressure are 6 to 10 times higher than the maximal dose of

phenylephrine or ephedrine administered intranasally. In the case of

phenylephrine hydrochloride, the comment stated that if an entire dose

of a 0.5-percent nasal spray, which contains 1.5 mg phenylephrine

hydrochloride, were ingested, it would amount to only a small fraction

of the Category I recommended oral dose of 10 mg for this drug. In the

case of 0.5 percent ephedrine sulfate, a typical adult dose of 0.6 mg

would be delivered and, 100 percent of the dose, if ingested, would

amount to only a small fraction of the Cough-Cold Panel's recommended

oral dose of 8 to 12 mg as a bronchodilator (41 FR 38312 at 38408).

The agency has reviewed the studies cited by one comment as well as

other pertinent information concerning the side effects caused by

topical nasal decongestants. Based on its review of the available data

and information, the agency concludes that the warning--concerning the

use of topical nasal decongestants in patients with heart disease, high

blood pressure, thyroid disease, and diabetes--as discussed in the

tentative final monograph (50 FR 2220 at 2222 to 2223) is appropriate

for topical nasal decongestant drug products containing ephedrine or

one of its salts, phenylephrine hydrochloride, naphazoline

hydrochloride, oxymetazoline hydrochloride, and xylometazoline

hydrochloride. The agency does not believe that the studies adequately

support the safe use of topical nasal decongestants in patients with

heart disease, high blood pressure, thyroid disease, or diabetes

without the supervision of a physician. Further, the agency's adverse

reaction data indicate that, after rebound congestion, cardiovascular

effects are among the most numerous adverse effects reported.

The agency has reviewed its adverse reaction report files (Ref. 21)

and finds that cardiovascular effects such as bradycardia, tachycardia,

hypertension, and hypotension have been reported for products

containing topical nasal decongestants, particularly for oxymetazoline.

In most of the cases of cardiovascular effects, the topical nasal

decongestant drug was reported to be the only drug used by the patient

and was believed to be the suspect drug. Based on these adverse

reaction files, the agency is concerned that certain individuals may be

more susceptible to developing cardiovascular effects when using

topical nasal decongestants. Further, although topical nasal

decongestant drugs are recommended for no more than 3 days use, the

agency is aware that excessive use of topical nasal decongestants does

occur (see comment 2 in section I.A. of this document). Such excessive

use could also increase the possibility that individuals with the

conditions listed in the warning might develop adverse effects.

The agency does not believe that the studies submitted by one of

the comments adequately support the safe use of topical nasal

decongestants containing ephedrine or one of its salts, phenylephrine

hydrochloride, naphazoline hydrochloride, oxymetazoline hydrochloride,

or xylometazoline hydrochloride in patients with heart disease, high

blood pressure, thyroid disease, or diabetes without the supervision of

a physician. A number of the studies (Refs. 1 through 8) were not

useful to evaluate topical effects of the nasal decongestants because

the drugs were administered by oral or injectable routes. In 11 of the

submitted studies (Refs. 9 through 19), nasal decongestants were

administered intranasally in subjects with cardiovascular disorders,

diabetes, or thyroid disease. In 1 of the 11 studies (Ref. 19), the

number of hypertensive subjects could not be determined. In the

remaining 10 studies, 833 subjects were studied but only 50 subjects

had the conditions referred to in the warning. Thus, the agency does

not consider this limited number of subjects adequate to support

deletion of the warning.

The data also show that the oral doses of some topical nasal

decongestants that are required to produce adverse reactions exceed the

recommended topical dosages; however, none of the submitted data

address the extent of absorption of nasal decongestants from the nasal

mucosa, and this may be more analogous to intravenous administration

than to oral administration of the drug. Many drugs (e.g., sublingual

nitroglycerin, nitroglycerin spray, corticosteroids) are absorbed well

from the mucosa of the oropharynx and can be more rapidly and

completely absorbed than when ingested orally.

Further, the submitted data do not contain sufficient information

to exclude the systemic effects alluded to in the warning. Actual data

on blood pressure changes were not provided in most of the studies, and

the degree of absorption of the drugs from topical intranasal

administration was not addressed. Although topical nasal decongestants

are administered in smaller doses than the oral doses of these drugs,

the safety of these drugs when used without physician supervision by

patients with heart disease, high blood pressure, thyroid disease,

diabetes, or difficulty in urination due to enlargement of the prostate

gland has not been adequately demonstrated.

Based on the above reasons, the agency is retaining the following

warning for topical nasal decongestant products containing ephedrine,

phenylephrine hydrochloride, naphazoline hydrochloride, oxymetazoline

hydrochloride, or xylometazoline hydrochloride that was proposed in the

tentative final monograph: ``Do not use this product if you have heart

disease, high blood pressure, thyroid disease, diabetes, or difficulty

in urination due to enlargement of the prostate gland unless directed

by a doctor.''

References

(1) Stockton, A.B., P.T. Pace, and M.L. Tainter, ``Some Clinical

Actions and Therapeutic Uses of Racemic Synephrine,'' Journal of

Pharmacology and Experimental Therapeutics, 41:11-20, 1931.

(2) Keys, A., and A. Violante, ``The Cardio-Circulatory Effects

in Man of Neo-Synephrin,'' Journal of Clinical Investigation, 21:1-

12, 1942.

(3) McLaurin, J.W., W.F. Shipman, and R. Rosedale, ``Oral

Decongestants--A Double Blind Comparison Study of the Effectiveness

of Four Sympathomimetic Drugs: Objective and Subjective,''

Laryngoscope, 71:54-67, 1961.

(4) Chen, K.K., and C.F. Schmidt, ``Ephedrine and Related

Substances,'' Medicine, 9:1-117, 1930.

(5) Drew, C.D.M. et al., ``Comparison of the Effects of D-(-)-

ephedrine and L-(+)-pseudoephedrine on the Cardiovascular and

Respiratory Systems in Man,'' British Journal of Clinical

Pharmacology, 6:221-225, 1978.

(6) Miller, T.G., ``A Consideration of the Clinical Value of

Ephedrine,'' The American Journal of the Medical Sciences, 170:157-

181, 1925.

(7) Edmonds, M.E., A.G. Archer, and P.J. Watkins, ``Ephedrine: A

New Treatment for Diabetic Neuropathic Oedema,'' The Lancet,

1(8324):548-551, 1983.

(8) Banner, A.S. et al., ``Arrhythmogenic Effects of Orally

Administered Bronchodilators,'' Archives of Internal Medicine,

139:434-437, 1979.

(9) Myers, M.G., and J.J. Iazzetta, ``Intranasally Administered

Phenylephrine and Blood Pressure,'' Canadian Medical Association

Journal, 127:365-368, 1982.

(10) Van Alyea, O.E., and W.A. Donnelly, ``Systemic Effects of

Intranasal Medication,'' The Eye, Ear, Nose, and Throat Monthly,

31:476-480, 1952.

(11) Green, M., ``Double-Blind Study of Nasal Decongestion with

Oxymetazoline and Phenylephrine in Asthmatic Children with

Rhinitis,'' Review of Allergy, 20:863-868, 1966.

(12) Bailey, B.J., ``Clinical Evaluation of a Topical Nasal

Decongestant--Oxymetazoline,'' The Eye, Ear, Nose, and Throat

Monthly, 48:512-515, 1969.

(13) Slodki, S.J., and C.A. Montgomery, ``Clinical Comparison of

Oxymetazoline and Ephedrine in Nasal Decongestion,'' Current

Therapeutic Research, 7(1):19-22, 1965.

(14) Cohen, B.M., and E.P. Duffy, ``Physiologic and Clinical

Estimates of the Relief of Nasal Flow Obstruction in Allergic

Rhinitis: Effects of a Topical Decongestant (Oxymetazoline),''

Journal of Asthma Research, 7(2):65-73, 1969.

(15) Bumbalo, T.S., ``Xylometazoline HCl--a New Nasal Medication

for Pediatric Use (an Evaluation),'' Western Medicine, 1:9-19, 1946.

(16) Kolodny, A.L., ``Ba-11391 (Otrivin), a New Imidazoline

Vasoconstrictor with Lessened Side Effects,'' Antibiotic Medicine

and Clinical Therapy, 6(8):152-457, 1959.

(17) Biesalski, P., and K. Marquart, ``Therapeutic Aspects of

Rhinitis in Early Childhood, Thermoelectrode Investigations with

Nasal Decongestants (``Zur Behandlungder Rhinitis im fruhen

Kindesalter. Thermoelektrische Untersuchungen an abschwellenden

Nasenmittein''),'' (English Translation), Schweizerische

Medizinische Wochenschrift, 89(19):510-512, 1959.

(18) Jacques, A.A., and V.H. Fuchs, ``A New Topical Nasal

Decongestant,'' The Journal of the Louisiana State Medical Society,

111:384-386, 1959.

(19) Hagen, W.J., and M.G. Trelles, ``A New Local Decongestant

of Unusually Low Toxicity,'' The Eye, Ear, Nose, and Throat Monthly,

39:56-57, 1960.

(20) ``Summary of Published Evidence Relating to the Issue of

Intranasally-Applied Decongestants and Possible Cardiovascular

Changes,'' The Proprietary Association, Washington, Appendix A of

Comment No. C206, Docket No. 76N-052N, Dockets Management Branch.

(21) Department of Health and Human Services, Food and Drug

Administration, ``Spontaneous Reporting System, Line Listing of

Adverse Reports: Nasal-76-93,'' 1976-1993, in OTC Vol. 04NFM, Docket

No. 76N-052N, Dockets Management Branch.

24. One comment contended that the proposed warnings in Sec. 341.80

for topical nasal decongestant sprays and drops (which state: ``Do not

use this product if you have heart disease, high blood pressure,

thyroid disease, diabetes, or difficulty in urination due to

enlargement of the prostate gland unless directed by a doctor;'' ``Do

not exceed recommended dosage because burning, stinging, sneezing, or

increase of nasal discharge may occur;'' and ``Do not use this product

for more than 3 days. If symptoms persist, consult a doctor.'') do not

apply to its company's ``innovative and unique one-way metered pump

spray delivery system.'' The comment explained that the metered

delivery system for its topical nasal decongestant drug products

substantially reduces dosage variability, assures uniform dosage and

spray pattern, and thereby further minimizes any possibility of

significant systemic absorption and systemic side effects. For this

reason, the comment recommended that for these products the agency

eliminate the warning in proposed Sec. 341.80(c)(2)(iii)(b) not to use

topical nasal decongestants if certain disease conditions are present.

Stating that the spray pattern achieved with the pump virtually

eliminates the nasal irritation and rebound congestion sometimes

associated with conventional sprays and drops and that marketing

experience has confirmed the purpose of the pump's design, the comment

also contended that the warnings proposed in Sec. 341.80(c)(2)(i)(a)

and (c)(2)(iii)(a) concerning burning, stinging, etc., and a

restriction to only 3 days' dosage should not be required for its

metered pump products.

The comment did not submit any data to support its contention that

the use of a metered pump delivery system makes the above mentioned

warnings unnecessary. Furthermore, the agency believes that regardless

of the uniformity of the dosage and spray pattern of a topical nasal

decongestant, the pharmacologic action of nasal decongestant active

ingredients can produce adverse reactions in some susceptible

individuals who have heart disease, high blood pressure, diabetes, etc.

Thus, in the interest of consumer safety, the warning proposed in

Sec. 341.80(c)(2)(iii)(b) would still be applicable, regardless of the

nasal spray delivery system. Also, a uniform dosage and spray pattern

would not eliminate the possibility of overuse of the topical nasal

decongestant drug product. An individual might use too much of the

spray by repeatedly applying the medication or by using the product

longer than the recommended 3 days use. Thus, rebound congestion could

occur and the warning in Sec. 341.80(c)(2)(iii)(a) would be applicable.

The agency is unaware of data to support the comment's contention that

a uniform dosage and spray pattern could help to lessen adverse effects

such as burning, stinging, sneezing, etc., which might be caused by an

excessive dose of a topical nasal decongestant. In the absence of data,

the agency cannot agree with the comment that the warning regarding

burning, stinging, sneezing in Sec. 341.80(c)(2)(i)(a) (redesignated as

Sec. 341.80(c)(2)(i)(B) in this final monograph) is unnecessary for its

pump spray delivery system. Therefore, the agency concludes that the

warnings for topical nasal decongestants mentioned by the comment are

applicable regardless of the spray delivery system.

The agency notes that a request of the type submitted by the

comment (for deletion of certain warnings for a specific metered pump

delivery system) could be considered as a request for an exemption from

the monograph requirements or as a request for a monograph deviation.

For an exemption, which would require the submission of a petition to

amend the final monograph, data would have to be submitted to support

the comment's contention that certain warnings are unnecessary for the

metered pump spray delivery system. An exemption from these warning

statements could then be included in the monograph for all nasal

decongestant ingredients marketed in the specified metered dose spray

dosage form along with the specifications for the specific metered pump

spray delivery system. The agency believes that it would be difficult

to write such specifications for inclusion in a monograph and thus

considers a monograph deviation to be a more suitable alternative. A

monograph deviation is covered by the regulations in 21 CFR 330.11.

These regulations provide for the submission of a limited new drug

application (NDA) covering only the deviation from the final monograph.

Under these regulations, data submitted in support of an NDA for a

product that deviates from an OTC drug final monograph must be in the

form required by 21 CFR 314.50. Also, the request must include a

statement that the product meets all conditions of the applicable OTC

drug monograph except for the deviation for which approval is

requested. The application may omit all information except that

pertinent to the deviation. For the particular product discussed in the

comment, the manufacturer should provide sufficient manufacturing

control data to assure FDA of the uniformity of the metered dose

delivery and of the spray pattern claimed for the drug product, and

should include adequate clinical data to confirm that the warnings are

unnecessary.

25. One comment recommended that the following statements be

allowed for topical nasal decongestants marketed in a one-way metered

pump delivery system: ``Won't draw back nasal fluids,'' ``unique one-

way pump prevents draw-back contamination,'' ``protects against draw-

back contamination,'' and ``unique metered spray delivers a controlled/

metered dose.'' In addition, the comment contended that ``accurate''

statements such as ``long lasting relief'' are appropriate for

oxymetazoline-containing nasal decongestant drug products.

The agency believes that information describing a metered dose

delivery system, such as that recommended by the comment, is product

specific and above and beyond the scope of the standards set by this

final monograph for OTC nasal decongestant drug products.

The OTC drug review program establishes conditions under which OTC

drugs are generally recognized as safe and effective and not

misbranded. Two principal conditions determined during the review are

allowable ingredients and the allowable labeling for those ingredients.

The FDA has determined that it is not practical--in terms of time,

resources, and other considerations--to set standards for all labeling

found in OTC drug products. Accordingly, OTC drug monographs regulate

only labeling related in a significant way to the safe and effective

use of drug products by consumers. OTC drug monographs establish the

allowable labeling for the following: the product statement of

identity; the names of active ingredients; the indications for use; the

directions for use; the warnings against unsafe use, side effects, and

adverse reactions; and the claims concerning the mechanism of drug

action. Accordingly, such information as that recommended by the

comment is outside the scope of the OTC drug review.

The agency emphasizes that even though such information is outside

the scope of the OTC drug review, it may be used in labeling subject to

the prohibitions in section 502 of the act relating to labeling that is

false or misleading. Such information will be evaluated by the agency

on a case by case basis in conjunction with normal enforcement

activities relating to that section of the act. Moreover, any

information that is outside the scope of the review, even though it is

truthful and not misleading, may not appear in any portion of the

labeling required by the monograph and may not detract from such

required information.

Regarding the comment's claim of ``long lasting relief'' for

oxymetazoline-containing nasal decongestant drug products, the agency

notes that oxymetazoline hydrochloride has a frequency of use of ``not

more often than every 10 to 12 hours'' which is the longest duration of

action of any topical nasal decongestant in the monograph. As stated in

the tentative final monograph for OTC nasal decongestant drug products,

the ``duration of effect has been included in the established dosages

and directions for these products by stating the frequency of use (in

terms of hours), which indirectly tells the consumer the duration of

the products' effects'' (50 FR 2220 at 2236). Although not included in

the monograph, the agency has no objection to a statement such as

``long lasting relief'' appearing in the labeling of an OTC nasal

decongestant drug product containing oxymetazoline hydrochloride.

However, as stated above, such statements are subject to the

prohibitions in section 502 of the act and may not appear in any

portion of the labeling required by the monograph and may not detract

from such required information.

26. Two comments suggested that the proposed warning for oral nasal

decongestants in Sec. 341.80(c)(1)(i)(a) and (c)(1)(ii)(a) (which

states: ``Do not exceed recommended dosage because at higher doses

nervousness, dizziness, or sleeplessness may occur.'') be revised. One

comment suggested revising the warning sections to state: ``Do not

exceed recommended dosage. If nervousness, dizziness, or sleeplessness

occur, discontinue use and consult a physician.'' This comment stated

that, as the warning presently reads, it might suggest to consumers

that nervousness, dizziness, and sleeplessness are the only

consequences of exceeding the recommended dose, which is not

necessarily so. The comment added that ``nervousness, dizziness, and

sleeplessness are significant enough to be a separate warning as they

may, on occasion, occur at the recommended dose.'' The second comment

suggested that the warning sections be rewritten to state: ``Do not

exceed recommended dosage. If nervousness, dizziness, or sleeplessness

occur, consult a doctor.'' The comment explained that a patient's

medical history information is needed before a doctor can appropriately

advise the patient whether to continue the same dose, decrease the

dose, or discontinue the drug if the above-mentioned symptoms occur.

The agency agrees with the comments that the warnings for oral

nasal decongestants proposed in Sec. 341.80(c)(1)(i)(a) and

(c)(1)(ii)(a) of the tentative final monograph could be revised to make

them separate statements. Both comments proposed the same first

statement, which is the same language as proposed in the tentative

final monograph and which the agency is adopting in this final

monograph. However, the comments differ in their suggested second

statement. The second comment did not state to discontinue use of the

drug if the above-mentioned symptoms occur. The agency believes that if

nervousness, dizziness, or sleeplessness occur with use of a nasal

decongestant drug, it is best to advise the consumer to discontinue use

of the drug as a safety measure, and to consult a doctor for advice. In

addition, in order to emphasize that the drug should not be overused,

the agency is requiring that the first part of the warning appear on

the label of the product in boldface type. Therefore, in the final

monograph, the warnings read as follows: ``Do not exceed recommended

dosage. [first sentence in boldface type] If nervousness, dizziness, or

sleeplessness occur, discontinue use and consult a doctor.''

27. One comment contended that the proposed warning for topical

nasal decongestants in Sec. 341.80(c)(2)(i)(a) (which states: ``Do not

exceed recommended dosage because burning, stinging, sneezing, or

increase of nasal discharge may occur.'') does not appear to be

justified on the basis of consumer information and should be deleted

from the monograph. The comment stated that one major firm reviewed its

consumer complaint file on nasal sprays over a period of 5 years and

found an average complaint rate of less than one complaint per million

packages sold. The comment added that other firms have reported similar

data. The comment questioned the logic of the cause and effect

statement contained in the warning as it applies to topical nasal

decongestant sprays and drops, i.e., that the reactions of ``burning,

stinging, sneezing, or increase of nasal discharge'' will be the result

of exceeding the recommended dosage. The comment argued that even if an

excessive amount of spray or drops is used, which seems highly

unlikely, the solution will either run out of the nose or drain to the

back of the throat or both. In either case, the comment indicated that

the amount of liquid that will adhere to the nasal mucosa is relatively

constant.

In the tentative final monograph for OTC nasal decongestant drug

products, the agency reviewed a related comment regarding the warning

``Do not exceed recommended dosage because burning, stinging, sneezing,

or increase of nasal discharge may occur.'' The agency concluded that

this warning statement should apply to all topical nasal decongestant

active ingredients administered as a drop, spray, jelly, or in an

inhalant dosage form. (See 50 FR 2220 at 2232 to 2233.)

The agency also reviewed the labeling of topical nasal decongestant

drug products previously approved under NDA's. The NDA labeling for

products containing the nasal decongestant active ingredient

oxymetazoline contained the statement: ``Local stinging and slight

burning can occur with any topical nasal decongestant'' (Ref. 1). The

NDA labeling for a product containing xylometazoline hydrochloride

contained the following statement in the ``Adverse Reactions'' section:

``Because of the pharmacological relationship among sympathomimetic

nasal decongestants, the following types of effects may occur: burning,

stinging, dryness of the nasal mucosa, sneezing; * * *.'' (Ref. 2).

Furthermore, the AMA ``Drug Evaluations Annual'' describes typical

adverse reactions of topical nasal decongestants as temporary

discomfort such as stinging, burning, or dryness of the nasal mucosa,

while the specific adverse reactions for naphazoline, oxymetazoline,

and xylometazoline include sneezing as well (Ref. 3). Thus, the agency

concludes that a warning concerning burning, stinging, sneezing, or an

increase in nasal discharge is supported by clinical evidence and that

the consumer complaint data, as presented by the comment, are

inadequate to substantiate deletion of such a warning from the

monograph. Based on the NDA labeling and AMA ``Drug Evaluations,'' the

agency believes that burning, stinging, sneezing, or an increase in

nasal discharge may occur at recommended dosages and has revised the

warning into two separate warnings to clarify that these side effects

can occur at recommended doses. Therefore, the following revised

warnings are being included in the final monograph: ``Do not exceed

recommended dosage,'' and ``This product may cause temporary discomfort

such as burning, stinging, sneezing, or an increase in nasal

discharge.'' Additionally, in order to emphasize that the drug should

not be overused, the agency is requiring that the warning ``Do not

exceed recommended dosage'' appear on the label of the product in

boldface type.

References

(1) Copy of FDA approved labeling from NDA 14-717, in OTC Vol.

04NFM, Docket No. 76N-052N, Dockets Management Branch.

(2) Copy of FDA approved labeling from NDA 11-919 in OTC Vol.

04NTFM, Docket No. 76N-052N, Dockets Management Branch.

(3) ``Drug Evaluations Annual,'' American Medical Association,

Milwaukee, WI, p. 408 and pp. 415-418, 1991.

28. One comment disagreed with the agency's proposed warning for

topical nasal decongestant drug products containing 1 percent

phenylephrine hydrochloride, which states: ``Frequent use of this

product may cause nasal congestion to recur or worsen.'' The comment

contended that the data in the two clinical studies (comparing the

safety and effectiveness of phenylephrine 1 percent vs. phenylephrine

0.5 percent) that were reviewed by the agency in the tentative final

monograph (50 FR 2220 at 2229) were insufficient to warrant the

proposed warning. The comment argued that the agency itself admits that

``* * * the differences in side effects between the two groups [0.5

percent vs. 1 percent phenylephrine] were not statistically

significant'' (50 FR 2229). The comment stated that one of the studies,

by Jolly et al. (Ref. 1), confirms this view by noting that ``The

higher incidence of responses which probably reflects rebound hyperemia

in the 1-percent group (19 percent) as compared to the 0.5-percent

group (4 percent) is of questionable significance from the statistical

standpoint.'' The comment added that Jolly et al. question the

reliability of the method used in the study for assessing side effects.

In addition, the comment contended that even if one were to assume that

the method of data collection on side effects used by Jolly et al. was

unquestionable, the two studies are not confirmatory in relation to the

``possible'' effect seen in the Jolly et al. study. The comment also

mentioned that critical information (i.e., the use of prestudy

medication and the baseline conditions of individuals who were reported

to have experienced the side effect of congestion during drug usage

periods) is missing from the assessment of side effects in these

studies.

In summary, the comment stated that the two clinical studies were

designed to assess efficacy, and the methodology was not sufficiently

sensitive to define confidently a comparative safety profile for the

two concentrations (0.5 and 1 percent) of phenylephrine. The comment

concluded that because the suggestive data form at best a possible link

of a side effect and are insufficient to warrant a label warning for

products containing 1 percent phenylephrine, the proposed warning

should not be included in the final monograph.

The agency disagrees with the comment that the two clinical studies

were designed to assess only effectiveness. Information in the

manufacturer's comment shows that the two clinical studies were

conducted to assess ``* * * the relative safety of the two

concentrations,'' and ``* * * to compare the tolerance exhibited * * *

to (0.5 and 1 percent phenylephrine hydrochloride nose drops) under

conditions of exaggerated (i.e., maximum limit of the present

recommended dosage) use'' (Ref. 2). In reviewing the Jolly et al. study

(Ref. 1), the agency observed that:

Twelve subjects who received the 1-percent concentration and 10

who received the 0.5-percent concentration experienced side effects

such as headache, nausea, dizziness, nasal edema, and erythema. The

differences in side effects between the two groups were not

statistically significant. However, FDA notes that the data did

suggest that the 1-percent concentration seemed more likely to

induce rebound congestion. The investigator also noted that the 0.5-

percent concentration may be slightly better tolerated (Ref. 3).

As discussed by the Cough-Cold Panel in its report, topical nasal

decongestants are known to cause rebound congestion with continued

frequent use (41 FR 38312 at 38396 to 38403). However, the Cough-Cold

Panel felt that the problem could be minimized if topical nasal

decongestants are administered in accordance with label directions at

recommended intervals for periods not exceeding 3 days (41 FR 38396).

Rebound congestion occurs when topical nasal decongestants (i.e., nasal

sprays, drops, jellies, and some inhalants) are used too often and for

too long a period of time. Prolonged and continued use of topical nasal

decongestants causes the nasal mucous membranes to become more

congested and swollen as the effect of the drug wears off. The

recurrence of congestion causes the user to reapply the drug. Repeated

applications of the drug cause the nasal passages to reopen, but only

briefly. This effect leads to continued use of the drug and perpetuates

the rebound phenomenon. As discussed in comment 2, the agency has

concluded that the 3-day use warning does not adequately explain to

consumers the problem of rebound congestion. Therefore, the agency is

clarifying the 3-day use warning as follows: ``Do not use this product

for more than 3 days. Use only as directed. Frequent or prolonged use

may cause nasal congestion to recur or worsen. If symptoms persist,

consult a doctor.'' These same revisions are being made in the 7-day

use warning for l-desoxyephedrine that appears in Sec. 341.80(c)(2)(ii)

of this final monograph.

Based on the above discussion, the agency is deleting the specific

warning for 1 percent phenylephrine hydrochloride that was proposed in

the tentative final monograph in Sec. 341.80(c)(2)(v) and is instead

requiring that 1 percent phenylephrine hydrochloride, as well as all

other topical nasal decongestants except l-desoxyephedrine, bear the

warning ``Do not use this product for more than 3 days. Use only as

directed. Frequent or prolonged use may cause nasal congestion to recur

or worsen. If symptoms persist, consult a doctor.'' This warning

appears in Secs. 341.80 (c)(2)(iii)(A), (c)(2)(v), (c)(2)(viii), and

(c)(2)(ix) of this final monograph.

The agency's detailed comments and evaluations of the data are on

file in the Dockets Management Branch (Ref. 3).

References

(1) Jolly, E. R. et al., ``Comparative Determination of Two

Formulations of Neosynephrine,'' draft of unpublished study, Comment

No. C0125, Docket No. 76N-0052, Dockets Management Branch.

(2) Comment No. C0125, Docket No. 76N-0052, Dockets Management

Branch.

(3) Letter from W. E. Gilbertson, FDA, to E. J. Hiross, Sterling

Drug, Inc., coded LET081, Docket No. 76N-052N, Dockets Management

Branch.

29. One comment stated that, to its knowledge, no studies exist

which show a definite association between the use of propylhexedrine

and the occurrence of rebound congestion. The comment stated that one

2-week study and a single-dose study cited by the Cough-Cold Panel show

that rebound congestion is not a problem with propylhexedrine, and a

third study was ambiguous and results only ``suggest a possible rebound

congestion'' (41 FR 38312 at 38402). The comment added that there are

no studies which conclude that 3 days is the duration of therapy which

reduces any risk of rebound congestion, and contended that the agency's

proposed 3-day use limitation warning in Sec. 341.80(c)(2)(vi) and

(c)(2)(x) is arbitrary and unsubstantiated. The comment recommended

that the agency revise proposed Sec. 341.80(c)(2)(vi) and (c)(2)(x) to

read: ``Not to be used for prolonged periods.''

The agency has reevaluated the studies cited by the comment (Refs.

1, 2, and 3). One study by Connell (Ref. 1) involved 64 adults with

nasal congestion associated with acute coryza. The study was designed

to compare the effect of a propylhexedrine inhaler on nasal airway

resistance measured before inhalation to develop baseline data and

after inhalation to measure the response pattern. With respect to this

study, the Cough-Cold Panel stated that ``measurements made 4 hours

after the initial inhalation, that is, 2 hours after the repeat

inhalation, suggest a possible rebound congestion'' (41 FR 38312 at

38402). In a single-dose study by Hamilton (Ref. 2), the nasal

decongestant effect of a propylhexedrine inhaler was compared with a

placebo inhaler in 50 adult subjects with nasal congestion due to head

cold. The subjects were divided equally between active and placebo

groups. This study concluded that drug action of the propylhexedrine

inhaler compared to placebo was demonstrated and that there were no

suggestions of adverse effects. The Cough-Cold Panel had reviewed this

study and stated that ``no side effects or evidence of rebound

congestion was noted'' (41 FR 38312 at 38402). Another study by Connell

(Ref. 3), which was not discussed by the Cough-Cold Panel, consisted of

a comparison between groups of normal volunteers assigned to active and

placebo inhalers (20 active and 10 placebo). Subjects were instructed

to use a dose of two inhalations per nostril every 4 hours during the

waking hours for a 2-week period. The study concluded that there were

no signs of ``rebound congestion'' in the 20 normal volunteers who used

the propylhexedrine inhaler every 4 hours for 2 weeks.

The agency agrees with the Cough-Cold Panel that the first study by

Connell (Ref. 1) does suggest rebound congestion. In addition, although

no rebound was seen with the single-dose study performed by Hamilton

(Ref. 2), this is not sufficient proof that rebound does not occur

because rebound is more likely to occur with repeated doses. The second

study by Connell (Ref. 3) was intended to measure rebound after use of

the propylhexedrine inhaler. Although the study concluded that there

were no signs of rebound in 20 normal volunteers, the agency believes

it would have been more meaningful if the study had included a number

of subjects with nasal congestion associated with head colds or acute

coryza as well as some subjects who used the recommended dose of two

inhalations every 2 hours for a number of days. Thus, the agency

believes that the second Connell study (Ref. 3) does not establish that

rebound congestion due to propylhexedrine inhalation under actual use

conditions does not occur.

Other references indicate that sympathomimetic amines can cause

rebound congestion (Refs. 4 and 5). For example, one source notes that

side effects of propylhexedrine include rebound congestion, headache,

and, in rare instances, an increase in blood pressure (Ref. 4). Another

source states that a major limitation of therapy with nasal

decongestants is that loss in efficacy and ``rebound'' hyperemia and

worsening of symptoms often occur with chronic use or when the drug is

stopped (Ref. 5).

Regarding the comment's contention that the 3-day use limitation

warning is arbitrary and unsubstantiated, the agency concluded in the

tentative final monograph that the 3-day warning is justified in view

of the Cough-Cold Panel's finding ``that nasal decongestants can

produce rebound congestion after a short period of use,'' i.e., 4 to 6

hours; as well as by prolonged use caused by habitual use for varying

periods of time (50 FR 2232). Moreover, the agency finds the comment's

suggested warning ``Not to be used for prolonged periods'' to be too

vague and indefinite. Because some individuals have a tendency to use

topical nasal decongestants for prolonged periods, the agency believes

that it is important to specifically state how long the product should

be used. Because rebound congestion can occur after a short period of

use, the agency believes that a 3-day use limitation provides a

reasonable period of time for relief of nasal congestion as well as an

adequate margin of safety against the development of rebound

congestion. Thus, the comment's recommendation is not being accepted.

The agency has determined that it is important to inform consumers

of the consequences of too frequent or prolonged use of propylhexedrine

or other topical nasal decongestants. Such products will have to bear

the following warning: ``Do not use this product for more than 3 days.

Use only as directed. Frequent or prolonged use may cause nasal

congestion to recur or worsen. If symptoms persist, consult a doctor.''

(See also comment 2 in section I.A. of this document and comment 28 in

section I.E. of this document.)

References

(1) Connell, J., ``Analysis of Study Designed to Characterize

`Benzedrex' Inhaler Response with Nasal Airway Resistance

Measurements and Nasal Congestion Ratings,'' draft of unpublished

study, in OTC Vol. 040253.

(2) Hamilton, L., ``Analysis of Study Designed to Characterize

Propylhexedrine Inhaler Activity as Measured by Nasal Airway

Resistance and Nasal Congestion Criteria,'' draft of unpublished

study, in OTC Vol. 040272.

(3) Connell, J., ``Analysis of Nasal Airflow Study Designed for

the Determination of `Rebound Congestion' from the `Benzedrex'

Inhaler,'' draft of unpublished study, in OTC Vol. 040272.

(4) Harvey, S. C., ``Sympathomimetic Drugs,'' in ``Remington's

Pharmaceutical Sciences,'' 18th ed., edited by A. R. Gennaro et al.,

Mack Printing Co., Easton, PA, p. 884, 1990.

(5) Hoffman, B. B., and R. J. Lefkowitz, ``Catecholamines and

the Sympathomimetic Drugs,'' in ``The Pharmacological Basis of

Therapeutics,'' 8th ed., edited by A. G. Gilman et al., Pergamon

Press, Inc., New York, p. 216, 1990.

II. Summary of Significant Changes From the Proposed Rule

1. In order to allow for flexibility in the labeling of products,

the agency has revised the indications in Sec. 341.80(b)(1) to allow

manufacturers to choose from among any of the indications (i.e., the

common cold (cold), allergic rhinitis, or sinusitis) for nasal

decongestant drug products that are consistent with the intended use of

the product. (See comment 14 in section I.E. of this document)

2. The agency is not including proposed Sec. 341.80(b)(2), ``Other

allowable indications'' in this final monograph, but is revising and

incorporating the statements proposed in that section of the tentative

final monograph into the indications included in Sec. 341.80(b)(2) of

this final monograph. (See comments 13 and 16 in section I.E. of this

document.)

3. Because the phrases ``For the temporary relief of'' and

``Temporarily relieves'' are interchangeable, the option of using

either phrase is included in Sec. 341.80(b) of the final monograph.

(See comment 15 in section I.E. of this document.)

4. The agency is including the term ``sinus congestion'' in the

indications in Sec. 341.80(b)(2)(iv) and (v), and the word

``temporarily'' has also been added so that the phrase reads: ``* * *

temporarily relieves sinus congestion and pressure.'' (See comments 16

and 17 in section I.E. of this document.)

5. In order to conform to numbering specified in 1 CFR 21.11(h),

the numbering of many of the warnings proposed in Sec. 341.80(c) has

been changed. Specifically, paragraphs (a) through (d) have been

designated as (A) through (D) in this final monograph. Likewise, in the

directions proposed in Sec. 341.80(d), paragraphs (a) and (b) have been

designated as (A) and (B).

6. The agency has revised the warning for oral nasal decongestants

in proposed Sec. 341.80(c)(1)(i)(a) and (c)(1)(ii)(a) (designated as

Sec. 341.80(c)(1)(i)(A) and (c)(1)(ii)(A) in this final monograph) to

provide the information in two separate statements. The agency is also

requiring that the first part of the warning appears on the label of

the product in boldface type so that

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