[Federal Register Volume 59, Number 162 (Tuesday, August 23, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-20456]
[[Page Unknown]]
[Federal Register: August 23, 1994]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Parts 310, et al.
Final Monograph for OTC Nasal Decongestant Drug Products; Final Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310, 341, and 369
[Docket No. 76N-052N]
RIN 0905-AA06
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug
Products for Over-the-Counter Human Use; Final Monograph for OTC Nasal
Decongestant Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
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 the warnings now 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.'' (See comment 26 in section I.E. of this document.)
7. The agency has revised the warning for oral nasal decongestants
in proposed Sec. 341.80(c)(1)(i)(b) and (c)(1)(ii)(b) (designated as
Sec. 341.80(c)(1)(i)(B) and (c)(1)(ii)(B) in this final monograph) to
delete the language that restricted use of the product to only 7 days.
The revised warning reads as follows: ``If symptoms do not improve
within 7 days or are accompanied by fever, consult a doctor.'' (See
comment 21 in section I.E. of this document.)
8. To be consistent with the wording of other warnings for
children, the agency has revised the warning proposed in
Sec. 341.80(c)(1)(ii)(c) (designated as Sec. 341.80(c)(1)(ii)(C) in
this final monograph), ``Do not give this product to children who have
heart disease, high blood pressure, thyroid disease, or diabetes unless
directed by a doctor,'' as follows: ``Do not give this product to a
child who has heart disease, high blood pressure, thyroid disease, or
diabetes unless directed by a doctor.'' Likewise, the warning proposed
in Sec. 341.80(c)(2)(ix)(b) (designated as Sec. 341.80(c)(2)(viii)(B)
in this final monograph), ``Do not use this product in children who
have heart disease, high blood pressure, thyroid disease, or diabetes
unless directed by a doctor,'' has been revised as follows: ``Do not
use this product in a child who has heart disease * * *.''
9. The agency has divided the warning for topical nasal
decongestants proposed in Sec. 341.80(c)(2)(i)(A) into two separate
warnings and is requiring that the first warning appear on the label of
the product in boldface type as follows: ``Do not exceed recommended
dosage.'' [sentence in boldface type] and ``This product may cause
temporary discomfort such as burning, stinging, sneezing, or an
increase in nasal discharge.'' These two warnings are being included in
the final monograph in Sec. 341.80(c)(2)(i)(A) and (c)(2)(i)(B),
respectively. Inclusion of these two warnings has necessitated a change
of proposed Sec. 341.80(c)(2)(i)(b) to Sec. 341.80(c)(2)(i)(C). (See
comment 27 in section I.E. of this document.)
10. To inform and warn consumers about the possibility of the
occurrence of rebound congestion with prolonged and excessive use of
topical nasal decongestants, the agency has expanded the warning in
proposed Sec. 341.80(c)(2)(iii)(a), Sec. 341.80(c)(2)(vi),
Sec. 341.80(c)(2)(ix), and Sec. 341.80(c)(2)(x) (designated as
Sec. 341.80(c)(2)(iii)(A), Sec. 341.80(c)(2)(v),
Sec. 341.80(c)(2)(viii), and Sec. 341.80(c)(2)(ix), respectively, in
this final monograph) 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.'' (See comment 2 in section I.A. of this document.)
11. The agency is deleting the warning proposed for 1 percent
phenylephrine hydrochloride in Sec. 341.80(c)(2)(v) and is instead
requiring that 1 percent phenylephrine bear the warning for all topical
nasal decongestants in Sec. 341.80(c)(2)(iii)(A). (See comment 2 in
section I.A. of this document and comment 28 in section I.E. of this
document.)
12. To be consistent with the drug interaction precaution statement
used for OTC antitussive and bronchodilator drug products, the agency
has revised Sec. 341.80(c)(1)(i)(d) (now designated as
Sec. 341.80(c)(1)(i)(D)) 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.
The drug interaction precaution statement in Sec. 341.80(c)(1)(ii)(d)
(now designated as Sec. 341.80(c)(1)(ii)(D)) is similarly revised 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.
(See comment 22 in section I.E. of this document.)
13. The agency is adding Sec. 341.80(d)(2)(iv)(A)(2) for 0.025-
percent aqueous oxymetazoline hydrochloride solution to provide for use
by children 2 to under 6 years of age, and removing Sec. 341.90(m).
(See comment 8 in section I.C. of this document.)
14. The agency is revising Sec. 341.80(d)(2)(vii)(A)(2) for 0.05-
percent aqueous xylometazoline hydrochloride solution to provide for
use by children 2 to under 6 years of age. The agency also is not
including proposed Sec. 341.90(n) in this final monograph. (See comment
8 in section I.C. of this document.)
15. The agency is adding the statement ``Use only recommended
amount.'' to the directions for oxymetazoline hydrochloride
(Sec. 341.80(d)(2)(iv)(A)(2)), xylometazoline hydrochloride
(Sec. 341.80(d)(2)(vii)(A)(2)), and phenylephrine hydrochloride
(Sec. 341.80(d)(2)(v)(A)(4)) products labeled for use by children 2 to
under 6 years of age. The agency is also requiring that such products
have either a calibrated dropper or a metered-dose spray that delivers
no more than a stated amount of drug per three drops or three sprays.
(See comment 8 in section I.C. of this document.)
16. The agency has revised the directions statements, where
appropriate, as follows: ``Adults and children 12 years of age and
over,''. The agency has added the phrase ``* * * and children 12 years
of age and over'' to the directions to clarify that the 12 years and
over age group should receive an adult dose.
17. The agency is not including proposed Sec. 341.80(e) (which
states: ``The word `physician' may be substituted for the word `doctor'
in any of the labeling statements above.'') in this final monograph
because the agency has amended Sec. 330.1 (21 CFR 330.1) to permit the
interchangeability of certain terms, including ``physician'' and
``doctor,'' in all OTC drug monographs. (See 59 FR 3998, January 28,
1994.)
18. The agency is revising the paragraph designations in Sec. 341.3
Definitions in that Sec. 341.3((e) and (f) are being changed to
Sec. 345.3(f) and (g), respectively) and is adding new Sec. 341.3(h)
for Calibrated dropper. (See comment 8 in section I.C. of this
document.)
19. The agency has determined that for an active ingredient to be
included in an OTC drug final monograph, it is necessary to have
publicly available chemical information that can be used by all
manufacturers to determine that the ingredient is appropriate for use
in their products. Because l-desoxyephedrine and racephedrine
hydrochloride are not currently standardized and characterized for
quality and purity in official compendia, i.e., the United States
Pharmacopeia (U.S.P.), they are not included in this final monograph.
However, should interested parties develop appropriate standards that
are included in the U.S.P., this final monograph will be amended to
include one or both of these ingredients. In the interim, the final
monograph will be reserved for entries for l-desoxyephedrine and
racephedrine hydrochloride as topical nasal decongestants. These
ingredients are being included in Sec. 310.545(a)(6)(ii)(B),
nonmonograph ingredients, until appropriate compendial standards are
developed.
III. The Agency's Final Conclusions on OTC Nasal Decongestant Drug
Products
Based on the available evidence, the agency is issuing a final
monograph establishing conditions under which OTC nasal decongestant
drug products are generally recognized as safe and effective and not
misbranded. Specifically, the following ingredients are included in
this final monograph as OTC oral nasal decongestants: Phenylephrine
hydrochloride, pseudoephedrine hydrochloride, and pseudoephedrine
sulfate. The following ingredients are included as topical nasal
decongestants: Ephedrine, ephedrine hydrochloride, ephedrine sulfate,
naphazoline hydrochloride, oxymetazoline hydrochloride, phenylephrine
hydrochloride, propylhexedrine, and xylometazoline hydrochloride. The
status of phenylpropanolamine preparations as an oral nasal
decongestant is deferred at this time. All other ingredients for OTC
nasal decongestant use in this rulemaking are considered nonmonograph
ingredients: Beechwood creosote (topical), bornyl acetate (topical),
camphor (topical), cedar leaf oil (topical), l-desoxyephedrine
(topical), ephedrine (oral), ephedrine hydrochloride (oral), ephedrine
sulfate (oral), racephedrine hydrochloride (oral/topical), eucalyptol/
eucalyptus oil (topical), menthol/peppermint oil (topical), allyl
isothiocyanate (mustard oil) (topical), thenyldiamine hydrochloride
(topical), thymol (topical), and turpentine oil (spirits of turpentine)
(topical). The agency has established 21 CFR 310.545 in which it lists
certain active ingredients that are not generally recognized as safe
and effective for certain OTC drug uses. The following ingredients are
presently listed in 21 CFR 310.545(a)(6)(ii) for nasal decongestant
drug products: Allyl isothiocyanate, camphor (lozenge), beechwood
creosote (oral), eucalyptol (lozenge), eucalyptol (mouthwash),
eucalyptus oil (lozenge), eucalyptus oil (mouthwash), menthol
(mouthwash), peppermint oil (mouthwash), thenyldiamine hydrochloride,
thymol, thymol (lozenge), thymol (mouthwash), and turpentine oil. In
this final rule, the agency is amending 21 CFR 310.545(a)(6)(ii) by
adding the following nasal decongestant ingredients: Beechwood creosote
(topical), bornyl acetate (topical), cedar leaf oil (topical), l-
desoxyephedrine (topical), ephedrine (oral), ephedrine hydrochloride
(oral), ephedrine sulfate (oral), and racephedrine hydrochloride (oral/
topical). These ingredients appear in new Sec. 310.545(a)(6)(ii)(B),
while previous Sec. 310.545(a)(6)(ii) is redesignated
Sec. 310.545(a)(6)(ii)(A). Any drug product marketed for use as an OTC
nasal decongestant that is not in conformance with the monograph (21
CFR part 341, subparts A, B, and C) is considered a new drug within the
meaning of section 201(p) of the act (21 U.S.C. 321(p)) and misbranded
under section 502 of the act and cannot be marketed for this use unless
it is the subject of an approved application. An appropriate citizen
petition to amend the monograph may also be submitted under 21 CFR
10.30.
No comments were received in response to the agency's request for
specific comment on the economic impact of this rulemaking (50 FR 2220
at 2238). FDA has examined the impacts of the final rule under
Executive Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-
354). Executive Order 12866 directs agencies to assess all costs and
benefits of available regulatory alternatives and, when regulation is
necessary, to select regulatory approaches that maximize net benefits
(including potential economic, environmental, public health and safety,
and other advantages; distributive impacts; and equity). The agency
believes that this final rule is consistent with the regulatory
philosophy and principles identified in the Executive Order. In
addition, the final rule is not a significant regulatory action as
defined by the Executive Order and so is not subject to review under
the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. This final rule will require some relabeling for
products containing monograph ingredients. Manufacturers will have 1
year to implement this relabeling. This final rule will also require
reformulation of any products containing beechwood creosote (topical),
bornyl acetate (topical), cedar leaf oil (topical), l-desoxyephedrine
(topical), ephedrine sulfate (oral), and racephedrine hydrochloride
(oral/topical). For all other nonmonograph ingredients listed above,
the effective date was May 7, 1991. The impact to the final rule
appears to be minimal. Accordingly, the agency certifies that the final
rule will not have a significant economic impact on a substantial
number of small entities. Therefore, under the regulatory flexibility
Act, no further analysis is required.
The agency is removing existing warning and caution statements in
Sec. 369.20 for ``NASAL PREPARATIONS: OIL BASE,'' ``NASAL PREPARATIONS
IN PLASTIC SPRAY CONTAINERS,'' ``NASAL PREPARATIONS: VASOCONSTRICTORS
(AMPHETAMINE, EPHEDRINE, EPINEPHRINE, METHAMPHETAMINE, AND OTHERS OF
SIMILAR ACTIVITY),'' ``PHENYLEPHRINE HYDROCHLORIDE PREPARATIONS, ORAL''
and the terms ``PHENYLEPHRINE HYDROCHLORIDE, HYDROXYAMPHETAMINE'' and
``AND OTHERS OF SIMILAR ACTIVITY'' in the entry ``NASAL PREPARATIONS:
VASOCONSTRICTORS (PHENYLEPHRINE HYDROCHLORIDE, HYDROXYAMPHETAMINE,
PHENYLPROPANOLAMINE, AND OTHERS OF SIMILAR ACTIVITY)'' because these
portions of the regulations are superseded by the requirements of the
nasal decongestant final monograph (21 CFR part 341).
List of Subjects
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 341
Labeling, Over-the-counter drugs.
21 CFR Part 369
Labeling, Medical devices, Over-the-counter drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
310, 341, and 369 are amended as follows:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301,
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C.
216, 241, 242(a), 262, 263b-263n).
2. Section 310.545 is amended by redesignating the text of
paragraph (a)(6)(ii) as paragraph (a)(6)(ii)(A), by adding new
(a)(6)(ii)(A) heading and paragraphs (a)(6)(ii)(B) and (d)(23), and by
revising paragraph (d) introductory text and paragraph (d)(1) to read
as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(6) * * *
(ii) Nasal decongestant drug products--(A) Approved as of May 7,
1991. * * *
(B) Approved as of August 23, 1995.
Bornyl acetate (topical)
Cedar leaf oil (topical)
Creosote, beechwood (topical)
l-desoxyephedrine (topical)
Ephedrine (oral)
Ephedrine hydrochloride (oral)
Ephedrine sulfate (oral)
Racephedrine hydrochloride (oral/topical)
* * * * *
(d) Any OTC drug product that is not in compliance with this
section is subject to regulatory action if initially introduced or
initially delivered for introduction into interstate commerce after the
dates specified in paragraphs (d)(1) through (d)(23) of this section.
(1) May 7, 1991, for products subject to paragraphs (a)(1) through
(a)(2)(i), (a)(3) through (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except
as covered by paragraph (d)(3) of this section), (a)(8)(i), (a)(9)
through (a)(10)(iii), and (a)(11) through (a)(18)(i) of this section.
* * * * *
(23) August 23, 1995, for products subject to paragraph
(a)(6)(ii)(B) of this section.
PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
3. The authority citation for 21 CFR part 341 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353,
355, 360, 371).
4. Section 341.3 is amended by adding new paragraphs (f), (g), and
(h) to read as follows:
Sec. 341.3 Definitions.
* * * * *
(f) Oral nasal decongestant drug. A drug that is taken by mouth and
acts systemically to reduce nasal congestion caused by acute or chronic
rhinitis.
(g) Topical nasal decongestant drug. A drug that when applied
topically inside the nose, in the form of drops, jellies, or sprays, or
when inhaled intranasally reduces nasal congestion caused by acute or
chronic rhinitis.
(h) Calibrated dropper. A dropper calibrated such that the volume
error incurred in measuring any liquid does not exceed 15 percent under
normal use conditions.
5. Section 341.20 is added to subpart B to read as follows:
Sec. 341.20 Nasal decongestant active ingredients.
The active ingredient of the product consists of any of the
following when used within the dosage limits and in the dosage forms
established for each ingredient:
(a) Oral nasal decongestants. (1) Phenylephrine hydrochloride.
(2) Pseudoephedrine hydrochloride.
(3) Pseudoephedrine sulfate.
(b) Topical nasal decongestants. (1) [Reserved]
(2) Ephedrine.
(3) Ephedrine hydrochloride.
(4) Ephedrine sulfate.
(5) [Reserved]
(6) Naphazoline hydrochloride.
(7) Oxymetazoline hydrochloride.
(8) Phenylephrine hydrochloride.
(9) Propylhexedrine.
(10) Xylometazoline hydrochloride.
6. Section 341.80 is added to subpart C to read as follows:
Sec. 341.80 Labeling of nasal decongestant drug products.
(a) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the product as a
``nasal decongestant.''
(b) Indications. The labeling of the product states, under the
heading ``Indications,'' the phrase listed in paragraph (b)(1) of this
section, as appropriate, and may contain any additional phrases listed
in paragraph (b)(2) of this section. Other truthful and nonmisleading
statements, describing only the indications for use that have been
established and listed in paragraphs (b)(1) and (b)(2) of this section,
may also be used, as provided in Sec. 330.1(c)(2) of this chapter,
subject to the provisions of section 502 of the Federal Food, Drug, and
Cosmetic Act (the act) relating to misbranding and the prohibition in
section 301(d) of the act against the introduction or delivery for
introduction into interstate commerce of unapproved new drugs in
violation of section 505(a) of the act.
(1) (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 paragraphs (b)(1) (i), (ii),
and (iii) of this section):
(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.''
(2) In addition to the information identified in paragraph (b)(1)
of this section, the labeling of the product may contain any (one or
more) of the following statements:
(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.''
(c) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings'':
(1) Oral nasal decongestants--(i) For products containing
phenylephrine hydrochloride, pseudoephedrine hydrochloride, or
pseudoephedrine sulfate identified in Sec. 341.20 (a)(1), (a)(2), and
(a)(3) when labeled for adults. (A) ``Do not exceed recommended dosage.
[first sentence in boldface type] If nervousness, dizziness, or
sleeplessness occur, discontinue use and consult a doctor.''
(B) ``If symptoms do not improve within 7 days or are accompanied
by fever, consult a doctor.''
(C) ``Do not take 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.''
(D) ``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.''
(ii) For products containing phenylephrine hydrochloride,
pseudoephedrine hydrochloride, or pseudoephedrine sulfate identified in
Sec. 341.20 (a)(1), (a)(2), and (a)(3) when labeled for children under
12 years of age. (A) ``Do not exceed recommended dosage. [first
sentence in boldface type] If nervousness, dizziness, or sleeplessness
occur, discontinue use and consult a doctor.''
(B) ``If symptoms do not improve within 7 days or are accompanied
by fever, consult a doctor.''
(C) ``Do not give this product to a child who has heart disease,
high blood pressure, thyroid disease, or diabetes unless directed by a
doctor.''
(D) ``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.''
(iii) For oral nasal decongestant products labeled for both adults
and children under 12 years of age. The labeling of the product
contains the warnings identified in paragraph (c)(1)(i) of this
section.
(2) Topical nasal decongestants--(i) For products containing any
topical nasal decongestant identified in Sec. 341.20(b) when labeled
for adults. (A) ``Do not exceed recommended dosage.'' [sentence in
boldface type]
(B) ``This product may cause temporary discomfort such as burning,
stinging, sneezing, or an increase in nasal discharge.''
(C) ``The use of this container by more than one person may spread
infection.''
(ii) [Reserved]
(iii) For products containing ephedrine, ephedrine hydrochloride,
ephedrine sulfate, naphazoline hydrochloride, oxymetazoline
hydrochloride, phenylephrine hydrochloride, or xylometazoline
hydrochloride identified in Sec. 341.20 (b)(2), (b)(3), (b)(4), (b)(6),
(b)(7), (b)(8), and (b)(10) when used as nasal sprays, drops, or
jellies and when labeled for adults. (A) ``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.''
(B) ``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.''
(iv) For products containing naphazoline hydrochloride identified
in Sec. 341.20(b)(6) at a concentration of 0.05 percent. ``Do not use
this product in children under 12 years of age because it may cause
sedation if swallowed.''
(v) For products containing propylhexedrine identified in
Sec. 341.20(b)(9) when used in an inhalant dosage form and when labeled
for adults. ``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.''
(vi) For products containing any topical nasal decongestant
identified in Sec. 341.20(b) when labeled for children under 12 years
of age. The labeling of the product contains the warnings identified in
paragraph (c)(2)(i) of this section.
(vii) [Reserved]
(viii) For products containing ephedrine, ephedrine hydrochloride,
ephedrine sulfate, naphazoline hydrochloride, oxymetazoline
hydrochloride, phenylephrine hydrochloride, or xylometazoline
hydrochloride identified in Sec. 341.20(b)(2), (b)(3), (b)(4), (b)(6),
(b)(7), (b)(8), and (b)(10) when used as nasal sprays, drops, or
jellies and when labeled for children under 12 years of age. (A) ``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.''
(B) ``Do not use this product in a child who has heart disease,
high blood pressure, thyroid disease, or diabetes unless directed by a
doctor.''
(ix) For products containing propylhexedrine identified in
Sec. 341.20(b)(9) when used in an inhalant dosage form and when labeled
for children under 12 years of age. ``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.''
(x) For topical nasal decongestant products labeled for both adults
and for children under 12 years of age. The labeling of the product
contains the applicable warnings identified in paragraphs (c)(2)(i),
(c)(2)(ii), (c)(2)(iii), and (c)(2)(v) of this section.
(d) Directions. The labeling of the product contains the following
information under the heading ``Directions'':
(1) Oral nasal decongestants--(i) For products containing
phenylephrine hydrochloride identified in Sec. 341.20(a)(1). Adults and
children 12 years of age and over: 10 milligrams every 4 hours not to
exceed 60 milligrams in 24 hours. Children 6 to under 12 years of age:
5 milligrams every 4 hours not to exceed 30 milligrams in 24 hours.
Children 2 to under 6 years of age: 2.5 milligrams every 4 hours not to
exceed 15 milligrams in 24 hours. Children under 2 years of age:
consult a doctor.
(ii) For products containing pseudoephedrine hydrochloride or
pseudoephedrine sulfate identified in Sec. 341.20 (a)(2) and (a)(3).
Adults and children 12 years of age and over: 60 milligrams every 4 to
6 hours not to exceed 240 milligrams in 24 hours. Children 6 to under
12 years of age: 30 milligrams every 4 to 6 hours not to exceed 120
milligrams in 24 hours. Children 2 to under 6 years of age: 15
milligrams every 4 to 6 hours not to exceed 60 milligrams in 24 hours.
Children under 2 years of age: consult a doctor.
(2) Topical nasal decongestants--(i) [Reserved]
(ii) For products containing ephedrine, ephedrine hydrochloride, or
ephedrine sulfate identified in Sec. 341.20(b) (2), (3), and (4)--(A)
Nasal drops or sprays--For a 0.5-percent aqueous solution. Adults and
children 12 years of age and over: 2 or 3 drops or sprays in each
nostril not more often than every 4 hours. Children 6 to under 12 years
of age (with adult supervision): 1 or 2 drops or sprays in each nostril
not more often than every 4 hours. Children under 6 years of age:
consult a doctor.
(B) Nasal jelly--For a 0.5-percent water-based jelly. Adults and
children 6 to under 12 years of age (with adult supervision): place a
small amount in each nostril and inhale well back into the nasal
passages. Use not more often than every 4 hours.
(iii) For products containing naphazoline hydrochloride identified
in Sec. 341.20(b)(6)--(A) Nasal drops or sprays--(1) For a 0.05-percent
aqueous solution. Adults and children 12 years of age and over: 1 or 2
drops or sprays in each nostril not more often than every 6 hours. Do
not give to children under 12 years of age unless directed by a doctor.
(2) For a 0.025-percent aqueous solution. Children 6 to under 12
years of age (with adult supervision): 1 or 2 drops or sprays in each
nostril not more often than every 6 hours. Children under 6 years of
age: consult a doctor.
(B) Nasal jelly--(1) For a 0.05-percent water-based jelly. Adults
and children 12 years of age and over: place a small amount in each
nostril and inhale well back into the nasal passages. Use not more
often than every 6 hours. Do not give to children under 12 years of age
unless directed by a doctor.
(2) For a 0.025-percent water-based jelly. Children 6 to under 12
years of age (with adult supervision): place a small amount in each
nostril and inhale well back into the nasal passages. Use not more
often than every 6 hours. Children under 6 years of age: consult a
doctor.
(iv) For products containing oxymetazoline hydrochloride identified
in Sec. 341.20(b)(7)--(A) Nasal drops or sprays--(1) For a 0.05-percent
aqueous solution. Adults and children 6 to under 12 years of age (with
adult supervision): 2 or 3 drops or sprays in each nostril not more
often than every 10 to 12 hours. Do not exceed 2 doses in any 24-hour
period. Children under 6 years of age: consult a doctor.
(2) A 0.025-percent aqueous solution in a container having either a
calibrated dropper or a metered-dose spray that delivers no more than
0.027 milligrams of oxymetazoline per three drops or three sprays.
Children 2 to under 6 years of age (with adult supervision): 2 or 3
drops or sprays in each nostril 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.
(B) Nasal jelly--For a 0.05-percent water-based jelly. Adults and
children 6 to under 12 years of age (with adult supervision): place a
small amount in each nostril and inhale well back into the nasal
passages. Use not more often than every 10 to 12 hours. Do not exceed 2
doses in any 24-hour period. Children under 6 years of age: consult a
doctor.
(v) For products containing phenylephrine hydrochloride identified
in Sec. 341.20(b)(8)--(A) Nasal drops or sprays--(1) For a 1-percent
aqueous solution. Adults and children 12 years of age and over: 2 or 3
drops or sprays in each nostril not more often than every 4 hours. Do
not give to children under 12 years of age unless directed by a doctor.
(2) For a 0.5-percent aqueous solution. Adults and children 12
years of age and over: 2 or 3 drops or sprays in each nostril not more
often than every 4 hours. Do not give to children under 12 years of age
unless directed by a doctor.
(3) For a 0.25-percent aqueous solution. Adults and children 6 to
under 12 years of age (with adult supervision): 2 or 3 drops or sprays
in each nostril not more often than every 4 hours. Children under 6
years of age: consult a doctor.
(4) A 0.125-percent aqueous solution in a container having either a
calibrated dropper or a metered-dose spray that delivers no more than
0.135 milligrams of phenylephrine per three drops or three sprays.
Children 2 to under 6 years of age (with adult supervision): 2 or 3
drops or sprays in each nostril not more often than every 4 hours. Use
only recommended amount. [previous sentence in boldface type] Children
under 2 years of age: consult a doctor.
(B) Nasal jelly--(1) For a 1-percent water-based jelly. Adults and
children 12 years of age and over: place a small amount in each nostril
and inhale well back into the nasal passages. Use not more often than
every 4 hours. Do not give to children under 12 years of age unless
directed by a doctor.
(2) For a 0.5-percent water-based jelly. Adults and children 12
years of age and over: place a small amount in each nostril and inhale
well back into the nasal passages. Use not more often than every 4
hours. Do not give to children under 12 years of age unless directed by
a doctor.
(3) For a 0.25-percent water-based jelly. Adults and children 6 to
under 12 years of age (with adult supervision): place a small amount in
each nostril and inhale well back into the nasal passages. Use not more
often than every 4 hours. Children under 6 years of age: consult a
doctor.
(vi) For products containing propylhexedrine identified in
Sec. 341.20(b)(9) when used in an inhalant dosage form. The product
delivers in each 800 milliliters of air 0.40 to 0.50 milligrams of
propylhexedrine. Adults and children 6 to under 12 years of age (with
adult supervision): 2 inhalations in each nostril not more often than
every 2 hours. Children under 6 years of age: consult a doctor.
(vii) For products containing xylometazoline hydrochloride
identified in Sec. 341.20(b)(10)--(A) Nasal drops or sprays--(1) For a
0.1-percent aqueous solution. Adults and children 12 years of age and
over: 2 or 3 drops or sprays in each nostril not more often than every
8 to 10 hours. Do not give to children under 12 years of age unless
directed by a doctor.
(2) A 0.05-percent aqueous solution in a container having either a
calibrated dropper or a metered-dose spray that delivers no more than
0.054 milligrams of xylometazoline per three drops or three sprays.
Children 6 to under 12 years of age (with adult supervision): 2 or 3
drops or sprays in each nostril not more often than every 8 to 10
hours. Children 2 to under 6 years of age (with adult supervision): 2
or 3 drops or sprays in each nostril 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.
(B) Nasal jelly--(1) For a 0.1-percent water-based jelly. Adults
and children 12 years of age and over: place a small amount in each
nostril and inhale well back into the nasal passages. Use not more
often than every 8 to 10 hours. Do not give to children under 12 years
of age unless directed by a doctor.
(2) For a 0.05-percent water-based jelly. Children 6 to under 12
years of age (with adult supervision): place a small amount in each
nostril and inhale well back into the nasal passages. Use not more
often than every 8 to 10 hours. Children under 6 years of age: consult
a doctor.
(viii) Other required statements--For products containing
propylhexedrine identified in Sec. 341.20(b)(9) when used in an
inhalant dosage form. (A) ``This inhaler is effective for a minimum of
3 months after first use.''
(B) ``Keep inhaler tightly closed.''
PART 369--INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND
DEVICES FOR OVER-THE-COUNTER SALE
7. The authority citation for 21 CFR part 369 continues to read as
follows:
Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 353, 355, 356, 357, 371).
Sec. 369.20 [Amended]
8. Section 369.20 Drugs; recommended warning and caution statements
is amended by removing the entries for ``NASAL PREPARATIONS: OIL
BASE,'' ``NASAL PREPARATIONS IN PLASTIC SPRAY CONTAINERS,'' ``NASAL
PREPARATIONS: VASOCONSTRICTORS (AMPHETAMINE, EPHEDRINE, EPINEPHRINE,
METHAMPHETAMINE, AND OTHERS OF SIMILAR ACTIVITY),'' ``PHENYLEPHRINE
HYDROCHLORIDE PREPARATIONS, ORAL,'' and the terms ``PHENYLEPHRINE
HYDROCHLORIDE, HYDROXYAMPHETAMINE'' and ``AND OTHERS OF SIMILAR
ACTIVITY'' in the entry ``NASAL PREPARATIONS: VASOCONSTRICTORS
(PHENYLEPHRINE HYDROCHLORIDE, HYDROXYAMPHETAMINE, PHENYLPROPANOLAMINE,
AND OTHERS OF SIMILAR ACTIVITY).''
Dated: August 4, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-20456 Filed 8-22-94; 8:45 am]
BILLING CODE 4160-01-P