[Federal Register Volume 67, Number 246 (Monday, December 23, 2002)]
[Rules and Regulations]
[Pages 78158-78172]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-32158]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 341

[Docket No. 76N-052G]
RIN 0910-AA01


Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug 
Products for Over-The-Counter Human Use; Final Monograph for 
Combination 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 that establishes conditions under 
which over-the-counter (OTC) cold, cough, allergy, bronchodilator, and 
antiasthmatic (cough-cold) combination drug products are generally 
recognized as safe and effective and not misbranded as part of its 
ongoing review of OTC drug products. FDA is issuing this final rule 
after considering public comments on the agency's proposed regulation 
(tentative final monograph) and new data and information on OTC cough-
cold combination drug products that have come to the agency's 
attention.

DATES: This regulation is effective December 23, 2004.

FOR FURTHER INFORMATION CONTACT: Cazemiro R. Martin or Gerald M. 
Rachanow, Center for Drug Evaluation and Research (HFD-560), Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-
2222.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published, under Sec.  330.10(a)(6) (21 CFR 330.10(a)(6)), an advance 
notice of proposed rulemaking to establish a monograph for OTC cold, 
cough, allergy, bronchodilator, and antiasthmatic drug products, 
together with the recommendations of the Advisory Review Panel on OTC 
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products 
(the Panel), which was the advisory review panel that evaluated these 
products. The agency's proposed regulation for OTC cough-cold 
combination drug products was published in the Federal Register of 
August 12, 1988 (53 FR 30522).
    Final rules for these OTC drug products were published in segments: 
Anticholinergic (50 FR 46582, November 8, 1985), bronchodilator (51 FR 
35326, October 2, 1986), antitussive (52 FR 30042, August 12, 1987), 
expectorant (54 FR 8494, February 28, 1989), antihistamine (57 FR 
58356, December 9, 1992), and nasal decongestant (59 FR 43386, August 
23, 1994). This document on combination drug products, general issues, 
and miscellaneous ingredients is the final segment. In response to the 
proposed rule for OTC cough-cold combination drug products, the agency 
received 21 comments, which are on public display in the Dockets 
Management Branch, Food and Drug Administration, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852. This final monograph addresses all comments 
and objections, except as discussed below.
    In the Federal Register of July 27, 1995 (60 FR 38636), FDA 
published a final rule establishing that cough-cold combination drug 
products containing theophylline are not generally recognized as safe 
and effective and are misbranded for OTC use. In the Federal Register 
of September 27, 2001 (66 FR 49276), FDA published a partial final rule 
for cough-cold combination drug products containing a bronchodilator, 
stating that combinations containing any oral bronchodilator and any 
analgesic(s) or analgesic-antipyretic(s), anticholinergic, 
antihistamine, oral antitussive, or stimulant active ingredient are not 
generally recognized as safe and effective and are misbranded for OTC 
use. The combinations in these two final rules are listed in Sec.  
310.545(a)(6)(iv)(B) and (a)(6)(iv)(D),

[[Page 78159]]

respectively (21 CFR 310.545(a)(6)(iv)(B) and (a)(6)(iv)(D)).
    This final rule does not address the combination of an oral 
bronchodilator and an expectorant or the combination of an oral 
bronchodilator and an oral nasal decongestant, which had not been 
previously classified. These two combination products will be addressed 
in a future issue of the Federal Register.
    In the tentative final monograph for OTC cough-cold combination 
drug products, the agency proposed that combinations containing 
promethazine hydrochloride be switched from prescription to OTC status 
for short-term use (7 days) for relief of symptoms of the common cold 
(53 FR 30522 at 30559). In response, the agency received a citizen 
petition from a consumer's group and comments from several physicians 
objecting to OTC status for promethazine-containing drug products. The 
major concern raised was that use of promethazine in children under 2 
years may be associated with the occurrence of sudden infant death 
syndrome, and that OTC availability could ``dramatically increase'' its 
``overuse'' in children this age. The petition also raised concerns 
about possible adverse neurological reactions with promethazine. 
Following discussion at a Pulmonary-Allergy Drugs Advisory Committee 
meeting on July 31, 1989, the agency announced that cough-cold drug 
products containing promethazine hydrochloride could not be marketed 
OTC under the monograph (54 FR 36762, September 5, 1989). Subsequently, 
the agency received additional data to support OTC status for 
promethazine combinations for relief of symptoms of the common cold 
(Refs. 1, 2, and 3). The agency has not completed its review of these 
data nor made a final decision at this time on OTC use of promethazine 
combinations for relief of symptoms of the common cold and will issue a 
final decision in a future issue of the Federal Register.
    In the Federal Register of April 9, 1996 (61 FR 15700), the agency 
published a final rule/enforcement policy establishing Sec.  341.70 (21 
CFR 341.70) for the use of diphenhydramine citrate and diphenhydramine 
hydrochloride as an antihistamine and an antitussive for treating 
concurrent symptoms in either a single-ingredient or combination drug 
product. That final rule permitted OTC marketing of such products 
pending completion of the current final rule.
    Some of the combinations in this final rule include cough-cold 
ingredients in combination with either systemic analgesic-antipyretic 
or topical oral anesthetic/analgesic and demulcent ingredients. The 
monographs for these OTC drug products have not been finalized to date. 
Topical oral analgesic-antipyretic active ingredients were proposed in 
part 343 (21 CFR part 343) in the tentative final monograph for OTC 
internal analgesic, antipyretic, and antirheumatic drug products (53 FR 
46204, November 16, 1988). Anesthetic/analgesic and demulcent active 
ingredients were proposed in part 356 (21 CFR part 356) in the 
tentative final monograph for OTC oral health care drug products (53 FR 
2436, January 27, 1988, and amended at 56 FR 48302, September 24, 
1991). The citations to parts 343 and 356 in this final rule refer to 
the proposed sections that appear in the tentative final monographs. 
When the final monographs are issued for those two classes of OTC 
drugs, crossreferences to applicable sections will be included in part 
341 (21 CFR part 341). If any changes occur in the monograph conditions 
in those tentative final monographs, they will be stated in the final 
monographs and any appropriate revisions that may need to be made in 
part 341 will also be stated in those final rules.
    The agency advises that on or after December 23, 2004, no OTC drug 
product that is subject to this monograph and that contains a 
nonmonograph condition may be initially introduced or initially 
delivered for introduction into interstate commerce unless it is the 
subject of an approved application or abbreviated 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 
as soon as possible.

II. The Agency's Conclusions on the Comments

A. General Comments on Cold, Cough, Allergy, Bronchodilator, and 
Antiasthmatic Drug Products

    (Comment 1) One comment noted a possible conflict between the use 
of the terms ``should'' in proposed Sec.  341.85(b)(1) and (b)(2) 
(which state: ``The following indication for analgesic-antipyretic 
ingredients should be used'') and ``must'' in proposed Sec.  
341.85(b)(3) (which states: ``Both indications in Sec.  341.85(b)(1) 
and (2) must be used.''). The comment requested clarification of the 
agency's intention and the impact on the ``flexibility'' policy in 
Sec.  330.1(c)(2) (21 CFR 330.1(c)(2)).
    The agency notes that the word ``should'' was used in proposed 
Sec.  341.85(b)(1) and (b)(2) to reflect the flexibility policy set 
forth in Sec.  330.1(c)(2) that is mentioned in the introductory 
paragraph under Sec.  341.85(b). The word ``must'' in proposed Sec.  
341.85(b)(3) indicated that both of the indications specified in Sec.  
341.85(b)(1) and (b)(2) are required when a manufacturer elects to make 
both claims for its product. Although the words ``should'' and ``must'' 
are not used in this final rule, when both claims appear in labeling, 
the exact wording in Sec.  341.85(b)(1) and (b)(2) need not be used 
because alternate wording in accord with Sec.  330.1(c)(2) may be used.

B. General Comments on Miscellaneous OTC Ingredients

    (Comment 2) One comment submitted published literature (Ref. 4) to 
support the effectiveness of ascorbic acid (vitamin C), which was 
classified in category III in the tentative final monograph (53 FR 
30522 at 30529), to reduce the duration and symptoms of the common 
cold. The comment contended that, although ascorbic acid may not 
prevent the common cold, there is considerable evidence indicating it 
is beneficial in reducing the duration and unpleasant symptoms of the 
common cold. The comment also submitted an unpublished study (Ref. 5) 
on the preventive effects of 500 milligrams (mg) ascorbic acid taken 
four times a day against naturally transmitted rhinovirus 16 in college 
students under strictly controlled conditions. The comment contended 
that preliminary results from this study show significant beneficial 
effects for several cold symptoms, such as cough.
    The agency has determined that the submitted studies do not contain 
sufficient detail to assess their value in establishing the 
effectiveness of ascorbic acid in reducing the duration or symptoms of 
the common cold. In 1990, the agency asked the author of the comment to 
provide additional information (Ref. 6): (1) A detailed critical 
appraisal of these studies in accordance with the content and format 
described in Sec.  314.50(d)(5) and (d)(6) (21 CFR 314.50(d)(5) and 
(d)(6)) (for clinical data and statistical analysis); and (2) a full 
report, including the protocol, complete patient data, and statistical 
analysis, of the rhinovirus study. This information was never provided. 
Thus, the agency is not including ascorbic acid in this final 
monograph.

[[Page 78160]]

    (Comment 3) One comment noted the American Academy of Pediatrics' 
(AAP) recommendation for safety closures for products with over 5 
percent ethanol (volume/volume (v/v)) (53 FR 30522 at 30529). The 
comment said the statutory authority to require child-resistant 
closures rests with the Consumer Product Safety Commission (CPSC) under 
the Poison Prevention Packaging Act of 1970, as mentioned in the 
tentative final monograph (53 FR 30522 at 30527). The agency notes that 
CPSC has published a final rule requiring child-resistant packaging for 
mouthwashes with 3 grams (g) or more of absolute ethanol per package 
(60 FR 4536, January 24, 1995).
    (Comment 4) One comment argued against the AAP recommendations to 
limit the alcohol content of cough-cold drug products not intended for 
use in households with children or not labeled for use in the pediatric 
population. (See cough-cold combination tentative final monograph, 
comment no. 16 (53 FR 30522 at 30528 to 30529).)
    The agency published a final rule for OTC drug products intended 
for oral ingestion that contain alcohol in the Federal Register of 
March 13, 1995 (60 FR 13590). In Sec.  328.10 (21 CFR 328.10), the 
agency established the following alcohol limitations in OTC drug 
products: (1) A 10-percent alcohol limit for OTC drug products intended 
for adults and children 12 years of age and over, (2) a 5-percent 
alcohol limit for OTC drug products intended for children 6 to under 12 
years of age, and (3) an 0.5-percent alcohol limit for OTC drug 
products intended for children under 6 years of age. That final rule 
was effective on March 13, 1996.
    (Comment 5) One comment responded to the agency's request in 
comment no. 14 of the tentative final monograph (53 FR 30522 at 30528) 
for information on the minimum concentration of menthol needed to 
achieve a: (1) Flavoring effect and (2) therapeutic effect. The comment 
stated that menthol is generally recognized as safe for use as a 
flavoring substance in the food additive regulations (Sec. Sec.  
172.515 and 182.20 (21 CFR 172.515 and 182.20)); there are no numerical 
minimum or maximum concentrations; and the only regulatory condition is 
that flavoring substances be used in the minimum quantity needed to 
produce their intended effect, which the comment defined as the desired 
organoleptic impact that achieves consumer acceptance of the product. 
The comment argued the same principle should apply to OTC drug products 
containing menthol as a flavoring agent.
    With respect to the minimum amount of menthol needed to achieve a 
therapeutic effect, the comment stated that the oral health care drug 
products tentative final monograph provides for topical oral 
anesthetic/analgesic use in a solid dosage form at a dose of 2 to 20 mg 
every 2 hours as needed (56 FR 48302 at 48344) and the antitussive drug 
products final monograph provides for a solid dosage form at a dose of 
5 to 10 mg every hour as needed (52 FR 30042 at 30056). The comment 
concluded that the distinction between menthol as a flavoring and 
therapeutic agent should be based on the types of claims that are made 
for menthol in product labeling. The comment contended that this 
approach may include the dual use of menthol as an active ingredient 
and as a flavor in the same product with appropriate claims for each 
use on the product label.
    The agency stated in the tentative final monograph for OTC cough-
cold combination drug products (53 FR 30522 at 30528) that if menthol 
is present at a therapeutic level in a product, it is considered an 
active ingredient in that product. Menthol is an OTC topical 
antitussive (Sec.  341.14(b)(2)) with a dosage in a lozenge of 5 to 10 
mg every hour as needed (Sec.  341.74(d)(2)(iii)). Combinations 
containing menthol used topically as an antitussive are included in 
Sec.  341.40 of this final monograph provided that the product is 
available in a solid dosage form to be dissolved in the mouth (see 
section I.D, comment no. 12 of this document). Menthol is also proposed 
as a topical oral anesthetic/analgesic in a solid dosage form in Sec.  
356.12(f) with a dosage of 2 to 20 mg every 2 hours as needed (proposed 
Sec.  356.52(d)(6)(ii), 56 FR 48302 at 48344). Proposed Sec.  356.26(a) 
through (e) (56 FR 48343) for topical oral anesthetic/analgesics 
include the combinations containing menthol with a dosage of 2 to 20 mg 
every 2 hours. If menthol were used only as a flavor in any of these 
antitussive or anesthetic/analgesic products, then it must be used at 
an amount less than the minimum dosage for the product's indication(s); 
otherwise it would be deemed to be present in the product at a 
therapeutic level and would be considered active.
    Section 172.515 of the food regulations states that flavoring 
substances and adjuvants may be safely used in foods when ``they are 
used in the minimum quantity required to produce their intended 
effect.'' Similarly, when menthol is used in OTC drug products as an 
inactive ingredient for flavoring purposes, the minimum quantity needed 
to produce the intended effect should be used. Use should also be in 
accord with Sec.  330.1(e) (21 CFR 330.1(e)), i.e., the inactive 
ingredient is safe in the amount administered and does not interfere 
with the effectiveness of the drug product or with suitable tests or 
assays to determine if the product meets its professed standards of 
identity, strength, quality, and purity.
    Because there is an effective dosage range, it is possible that 
menthol could be present in an antitussive or anesthetic/analgesic drug 
product both as an active ingredient and as a flavor. In such a 
situation, the agency would consider all of the menthol present to be 
an active ingredient, and menthol should be listed in the product's 
labeling as an active ingredient. However, the product could still 
state in its labeling that it is menthol flavored. In either case 
(antitussive or anesthetic/analgesic drug product), the total amount of 
menthol in the product cannot exceed the upper dosage limit stated in 
either monograph based on the product's labeled use(s).
    (Comment 6) One comment requested clarification of the acceptable 
level of turpentine oil as an inactive ingredient in an ointment 
combination product applied topically to the chest as an antitussive. 
The comment stated that the agency did not consider turpentine oil to 
be an inactive ingredient because of its high concentration (4.7 
percent weight/weight (w/w)) in the product (53 FR 30522 at 30550) and 
had previously indicated that 2 percent w/w was an acceptable level for 
turpentine oil as an inactive ingredient in the product (Ref. 7).
    As the comment noted, the agency previously reviewed this matter 
(Refs. 7, 8, and 9) and determined that 2 percent or less w/w was an 
acceptable level of turpentine oil as an inactive ingredient in these 
ointment products. This use of turpentine oil as an inactive 
ingredient, e.g., as a fragrance or for tactile properties, in these 
OTC drug products should be in the minimum quantity needed to produce 
the intended effect.

C. General Comments on OTC Cough-Cold Combination Drug Products

    (Comment 7) One comment referred to comment no. 60 in the tentative 
final monograph for OTC cough-cold combination drug products (53 FR 
30522 at 30550), concerning ``irreconcilable'' pediatric dosages for 
OTC cough-cold/ internal analgesic-antipyretic combinations. 
Referencing the agency's notice of intent on pediatric dosing 
information for OTC drug products (53 FR 23180, June 20, 1988), the 
comment asked the agency to

[[Page 78161]]

consider both weight-related and age-related pediatric dosage ranges 
for ingredients in OTC cough-cold combination drug products in that 
rulemaking.
    The agency intends to address pediatric dosing issues for OTC 
cough-cold/internal analgesic-antipyretic combination drug products in 
a future issue of the Federal Register. For OTC cough-cold combination 
drug products containing oral analgesic-antipyretic active ingredients, 
this final rule applies only to the directions for adults and children 
12 years of age and over; the directions for children under 12 years of 
age are deferred and do not need to conform to the directions in part 
341 at this time.
    (Comment 8) One comment mentioned an earlier request that the 
effective date for reformulation and relabeling of combination drug 
products containing ingredients from more than one monograph be the 
effective date of the last applicable final monograph. Noting that the 
agency had rejected this approach, the comment requested the agency to 
reconsider synchronization of effective dates for interrelated 
ingredients to minimize the resource burden and economic impact of 
possible multiple reformulations and ultimately to benefit consumers.
    As the comment noted, the agency previously addressed this issue in 
the tentative final monograph for OTC cough-cold combination drug 
products (53 FR 30522 at 30554, comment no. 65). The agency stated 
there that its policy is that an OTC drug product, whether single 
ingredient or combination, must conform to an applicable monograph on 
the effective date of the final monograph. The agency has reconsidered 
this issue, as the comment requested, but concludes there is no need to 
change its policy on cough-cold combination product reformulations. All 
of the final monographs for the different pharmacologic classes of OTC 
cough-cold ingredients have been issued and are currently effective. 
Therefore, most currently marketed OTC combination drug products that 
contain only cough-cold ingredients should now contain monograph 
ingredients and labeling.
    A few combination products containing only cough-cold ingredients 
and a few cough-cold combinations that contain internal analgesic or 
oral health care active ingredients may need reformulation of the 
cough-cold component(s) covered by part 341 and Sec.  310.545(a)(6). 
However, the internal analgesic or oral health care ingredient(s) in 
the combination product is/are not affected by this final rule. 
Manufacturers have 24 months to relabel combination products containing 
only cough-cold ingredients. The date for relabeling cough-cold 
combination products that contain internal analgesic or oral health 
care active ingredients will be specified in those final monographs.

D. Comments on Specific OTC Cough-Cold Combination Drug Products

    (Comment 9) One comment stated that the table for combination drug 
products (53 FR 30522 at 30556 and 30557) lists analgesic-
antipyretic(s) and an oral antitussive as a category I combination, 
while proposed Sec.  341.40 Permitted combinations of active 
ingredients does not list this combination. The comment believed this 
was an oversight, and requested that an appropriate subsection be 
created in proposed Sec.  341.40 to include this combination.
    The agency is correcting this oversight by amending Sec.  341.40 to 
include this combination.
    (Comment 10) One comment was concerned that proposed Sec.  341.40 
did not specifically provide for cough-cold combinations with buffered 
aspirin and requested the agency amend the appropriate paragraphs of 
Sec.  341.40 to include the phrase ``or buffered aspirin or aspirin and 
antacid combinations.''
    The tentative final monograph for cough-cold combination drug 
products was published before the internal analgesic tentative final 
monograph, and at that time the agency could not identify specific 
sections for the internal analgesic ingredients in these combinations. 
These sections can now be identified for all combinations that can 
contain buffered aspirin or aspirin and antacid combinations. Section 
341.40(a), (c), (f), (g), (l), (m), (n), (o), (q), and (r) of this 
final monograph will be amended in the future to identify the specific 
section numbers for internal analgesic ingredients, including buffered 
aspirin and aspirin and antacid combinations, when the final monograph 
for OTC internal analgesic-antipyretic drug products is published in 
the future.
    (Comment 11) One comment disagreed with the category III 
classification of combinations containing caffeine as a ``sedative 
corrective'' (an active ingredient specifically intended to counteract 
a side effect of other ingredients in the product). The comment noted 
that antihistamines are labeled with the warnings ``May cause 
drowsiness'' and ``Use caution when operating a motor vehicle or 
operating machinery'' (50 FR 2200 at 2208, January 15, 1985). The 
comment argued that caffeine should not be excluded from combinations 
containing an antihistamine to treat the common cold because of the 
double-edged sedative effect of common cold lethargy and the ingestion 
of the antihistamine. Noting two products containing an antihistamine 
and caffeine marketed for 17 years with no complaints of drowsiness and 
no reports of ineffectiveness, the comment asked the agency to 
reclassify as category I combinations of an antihistamine and over 90 
mg caffeine as a sedative corrective.
    The agency disagrees with the comment. The Panel agreed with the 
rationale for caffeine serving as a ``stimulant corrective'' (the 
Panel's term), but placed combinations containing caffeine in category 
III until such ``corrective'' pharmacological action could be proven 
(41 FR 38312 at 38325). The agency concurred in the tentative final 
monograph for OTC cough-cold combination drug products (53 FR 30522 at 
30543) and noted that no further data had been submitted to support the 
effectiveness of caffeine as a ``sedative corrective'' (the agency's 
term). No additional data were submitted after publication of the 
tentative final monograph for OTC cough-cold combination drug products. 
The marketing information provided by the comment regarding the two 
products containing both an antihistamine and caffeine that have been 
marketed for 17 years is supportive, but no clinical data were 
submitted. The agency considers the marketing information alone 
insufficient to justify inclusion of caffeine in a cough-cold 
combination to combat the drowsiness associated with antihistamine use 
or the ``lethargy'' that may accompany the common cold.
    (Comment 12) One comment asked that proposed Sec.  341.40(j), for 
oral antitussive active ingredients in Sec.  341.14(a), be expanded to 
include topical antitussive active ingredients in Sec.  341.14(b) in 
combination with any single or approved combination of topical oral 
anesthetic/analgesic active ingredients proposed in Sec. Sec.  356.10 
or 356.20 of the tentative final monograph for OTC oral health care 
drug products (53 FR 2436 at 2458). The comment noted that proposed 
Sec.  356.20 permits combinations of anesthetic/analgesic ingredients 
such as benzocaine with menthol and benzocaine with phenol and, thus, a 
category I topical antitussive ingredient (e.g., menthol) should also 
be permitted to be combined with appropriate anesthetic/analgesic 
ingredients such as benzocaine. The comment noted that proposed Sec.  
341.40(j) included only

[[Page 78162]]

single oral anesthetic/analgesic ingredients and requested that oral 
antitussives be allowed to be combined with allowed oral anesthetic/
analgesic combinations.
    The Panel reviewed data relating to combination drug products 
containing cough-cold and oral health care active ingredients with 
claims for relief of sore throat (41 FR 38312 at 38325). The Panel 
established specific criteria for the treatment of symptoms with 
combination products and based its category I recommendations on 
whether the combination of ingredients is rational concurrent therapy 
for a significant and existing population. The majority of the data the 
Panel reviewed were for combinations containing anesthetic/analgesic 
and cough-cold ingredients. The Panel determined that products 
containing an antitussive or a nasal decongestant combined with a 
topical oral anesthetic/analgesic in a lozenge dosage form are 
rational, identified a target population that would benefit from such 
products, and recommended classifying such products in category I (41 
FR 38312 at 38325). The agency concurred with the Panel in the 
tentative final monograph for OTC cough-cold combination drug products 
(53 FR 30522 at 30536 and 30537).
    In the rulemaking for OTC oral health care drug products, the 
agency proposed in Sec.  356.26(e) and (f) to allow combinations of 
benzocaine with menthol or phenol in oral anesthetic/analgesic 
combination drug products (56 FR 48302 at 48343). Thus, the agency 
agrees that menthol can be combined with benzocaine and that menthol in 
such a combination could be an antitussive, an oral anesthetic/
analgesic, or both.
    In the tentative final monograph for OTC cough-cold combination 
drug products, the agency determined that combinations containing 
anesthetic/analgesic and cough-cold ingredients could be rational only 
if the combination drug product is in a solid dosage form so that the 
anesthetic/analgesic ingredient may exert its topical effect and the 
oral antitussive can be ingested (53 FR 30522 at 30536 and 30537). 
However, menthol can be used in a solid dosage form that is dissolved 
in the mouth to provide topical antitussive action. The agency 
classified camphor as category I for topical (ointment) or steam 
inhalant antitussive use (52 FR 30042 at 30056), but camphor as a 
single ingredient in Sec.  341.14(b)(1) is limited to ointment and 
steam inhalation use.
    Although the comment suggested revisions of Sec.  341.40(j) only, 
the types of changes requested also apply to proposed Sec.  341.40(q), 
(u), (w), (x), and (z) (redesignated as paragraphs (t), (w), (y), (z), 
and (bb), respectively), which include various combinations of an oral 
antitussive, and/or an anesthetic/analgesic, and/or an oral demulcent 
active ingredient. The agency is allowing the combinations specified in 
these paragraphs to be available in either a liquid (to be swallowed) 
or solid dosage form (to be dissolved in the mouth and swallowed) 
provided the antitussive is an oral (systemic) antitussive ingredient 
identified in Sec.  341.13(a). (See section I.E, comment no. 18 of this 
document.) However, in this final monograph the agency is limiting any 
single topical antitussive active ingredient identified in Sec.  
341.14(b)(2) in combination drug products specified in Sec.  341.40(k), 
(t), (w), (y), (z), and (bb) to a solid dosage form to be dissolved in 
the mouth and swallowed.
    Menthol is used both as an antitussive and an oral health care 
anesthetic/analgesic. The agency has determined that an ingredient 
having multiple, concurrent uses can include that information in 
product labeling where appropriate (61 FR 15700, April 9, 1996). The 
statements of identity, indications, and warnings for concurrent use 
may be combined to eliminate duplicative words or phrases so that the 
resulting information is clear and understandable (60 FR 10286 at 
10290, February 23, 1995). For concurrent use of menthol, the statement 
of identity would be ``cough suppressant/oral anesthetic'' or 
``antitussive (cough suppressant)/oral anesthetic.'' Indications, 
warnings, and directions would be combined from Sec.  341.74(b), (c), 
and (d) and Sec.  356.52(b), (c), and (d).
    The antitussive directions are 5 to 10 mg every hour as needed, 
while the anesthetic/analgesic directions are 2 to 20 mg every 2 hours. 
The agency's policy is that when there is a difference in the 
directions established for the individual ingredients in a combination 
drug product, e.g., when the time intervals or age limitations for 
administration of the individual ingredients differ, the directions for 
a combination product may not exceed any maximum dosage limits 
established for the individual ingredients in the applicable OTC drug 
monograph (53 FR 30522 at 30554). This policy also applies when an 
ingredient is being labeled for dual use in a single product. Under 
this rationale, the every 2 hours directions for anesthetic/analgesic 
use would be controlling. The problem arises, however, that amounts of 
menthol from 2 mg up to 5 mg are not monograph dosages for menthol for 
antitussive use. Therefore, the agency has determined that appropriate 
directions for menthol when labeled for both uses in a product is 5 to 
10 mg every 2 hours. Interested parties may comment on this dosage and 
provide data and information to support an alternate dosage, using the 
citizen petition procedure in Sec.  10.30.
    Based on the discussion above and in section II.E, comment no. 18 
of this document, the agency is including the topical antitussive 
menthol in combinations specified in Sec.  341.40(k), (t), (w), (y), 
(z), and (bb) of this final monograph. Menthol as a topical antitussive 
can only be available in a solid dosage form when combined with any 
topical oral anesthetic/analgesic active ingredient. For oral 
antitussive-anesthetic/analgesic combinations, the directions for the 
individual ingredients are different and the directions for the 
combination may not exceed any maximum dosage limits, which includes 
dosing intervals, for any individual ingredient.
    (Comment 13) Four comments requested that a four-ingredient 
combination containing an analgesic-antipyretic, antitussive, 
expectorant, and oral nasal decongestant be included in the monograph. 
The comments stated that this combination is supported by the rationale 
underlying various two, three, and four-ingredient combinations 
containing these components that were proposed as category I in the 
tentative final monograph (53 FR 30522 at 30561). One comment requested 
that the combination of an analgesic-antipyretic, expectorant, and oral 
nasal decongestant be classified as category I based on related 
proposed category I combinations (53 FR 30522 at 30561).
    Another comment referred to comment no. 47 of the tentative final 
monograph (53 FR 30522 at 30540), where the agency proposed to classify 
in category I a combination containing an analgesic-antipyretic, 
antihistamine, oral antitussive, and oral nasal decongestant. The 
comment stated that, because the agency considers that an expectorant 
can be added to an analgesic-antipyretic in order to provide a product 
that will reduce fever and facilitate expulsion of bronchial 
secretions, and because the agency also considers that an expectorant 
can be added to an oral antitussive and oral nasal decongestant to 
control symptoms of excess bronchial and nasal secretions and cough, 
then it is rational to allow a combination containing an analgesic-
antipyretic, oral antitussive, expectorant, and oral nasal decongestant 
that would not only control symptoms

[[Page 78163]]

of excess bronchial and nasal secretions and cough, but also fever that 
might accompany such symptoms.
    One comment submitted five studies (two prospective epidemiological 
studies (Refs. 10 and 11), one retrospective epidemiological study 
(Ref. 12), and two consumer surveys (Refs. 13 and 14)) to demonstrate 
that a clinically significant target population exists that would 
require the use of the combination of an analgesic-antipyretic, 
antitussive, expectorant, and nasal decongestant to relieve concurrent 
symptoms of the common cold. One prospective epidemiological study 
(Ref. 10) included 373 colds studied in 293 subjects. The study results 
indicated that subjects in 56 percent of the cases had dry cough, nasal 
congestion, and aches (i.e., sore throat, headache, or achiness) for 1 
or more days of a cold, and 29 percent had the symptoms for 3 or more 
days.
    The second prospective epidemiological study (Ref. 11) was a 
multisite, upper respiratory survey by 14 pediatricians in 14 cities 
across the United States. The study included 3,166 male and female 
subjects, 2 to 12 years of age, who were treated by pediatricians 
during the winter of 1981 to 1982. On the day of first examination by 
the pediatrician, 12 percent of the subjects concurrently had dry 
cough, nasal congestion, and symptoms that would ordinarily require an 
analgesic-antipyretic. While severity of symptoms was not directly 
addressed, it was presumed the subjects had symptoms of sufficient 
severity or duration to visit a physician.
    The retrospective epidemiological study (Ref. 12), previously 
submitted to the agency to support the combination of an analgesic-
antipyretic, antihistamine, antitussive, and nasal decongestant, was 
discussed in the tentative final monograph for cough-cold combination 
drug products (53 FR 30522 at 30540 to 30541). The comment's data 
analysis showed symptoms of dry cough, pain, and nasal congestion 
(without the antihistamine symptoms) occurred concurrently in at least 
31 percent of this study population. Although less than half of the 
subjects (42.8 percent) documented symptom severity, 27.8 percent of 
those subjects rated severity moderate to severe.
    One consumer survey (Ref. 13) included data from telephone 
interviews with 322 people, 10 years of age or older, suffering from 
colds. At least 29.8 percent of the subjects concurrently had nasal/
head congestion, pain/fever/sore throat, and cough/phlegm for 1 or more 
days, and 10.5 percent of the subjects had these symptoms for 3 or more 
days. The comment stated that the incidence of dry cough among subjects 
with the four concurrent symptoms remained high (25.8 percent on day 1 
and 38.5 percent on day 7), while the incidence of dry cough among all 
subjects with colds declined (from 25.8 percent on day 1 to 12.4 
percent on day 7).
    The second consumer survey (Ref. 14) included 2,297 adults and 
1,423 children 6 to 17 years of age. Female heads of household 
identified the most severe symptoms of the cold or flu sufferer. The 
survey showed 25 percent of adults and 15 percent of children with 
colds and 37 percent of adults and 36 percent of children with flu 
reported four concurrent symptoms of coughing, chest congestion, nasal 
congestion, and sore throat.
    The agency has reviewed these data and other information and agrees 
they are adequate to include the following two combinations in this 
final monograph: (1) Analgesic-antipyretic, expectorant, and nasal 
decongestant and (2) analgesic-antipyretic, antitussive, expectorant, 
and nasal decongestant. The data showed there is a population with 
multiple cough-cold symptoms who benefit from these specific three or 
four ingredient combinations (Ref. 15).
    (Comment 14) One comment requested category I status for the nasal 
decongestant combination of l-desoxyephedrine and an aromatic mixture 
containing camphor, menthol, bornyl acetate, and lavender oil, which 
did not include the ingredient methyl salicylate as proposed in Sec.  
341.40(s) (53 FR 30522 at 30546 and 30547). The comment noted 
consumers' concerns about salicylates and contended: (1) The deletion 
of methyl salicylate from the aromatic mixture does not affect to a 
measurable extent the effectiveness, manufacture, product stability, or 
safety of this product, and (2) the revised combination product is 
still consistent with the agency's ``General Guidelines for OTC Drug 
Combination Products'' (Ref. 16). The comment subsequently informed the 
agency that bornyl acetate is an inactive ingredient in the product.
    The data (Ref. 17) that led to category I status for l-
desoxyephedrine as a single ingredient and when combined with the 
aromatic mixture did not include any studies of the combination using 
the aromatic mixture without methyl salicylate or bornyl acetate. The 
combination contains 11 mg methyl salicylate and 0.2 mg bornyl acetate. 
The agency accepts the comment's statement that bornyl acetate is an 
inactive ingredient in this product because of the insignificant amount 
that is present. However, the agency is concerned about deletion of the 
11 mg of methyl salicylate. While such a revised combination might be 
consistent with the agency's general guidelines (Ref. 16), without data 
showing that methyl salicylate does not make a contribution to the 
overall nasal decongestant effectiveness of the combination, the agency 
has no evidence that the aromatic mixture without methyl salicylate has 
the same effect when combined with l-desoxyephedrine. Therefore, the 
agency is including the combination proposed in Sec.  341.40(s) in this 
final monograph with deletion of the bornyl acetate but not with 
deletion of the methyl salicylate. The agency notes that the name for 
l-desoxyephedrine is now levmetamfetamine, and there is a compendial 
monograph for lavender oil (Ref. 18).
    (Comment 15) One comment submitted data (Ref. 19) to support the 
reclassification of the combination of camphor, eucalyptus oil, and 
menthol from category III to category I for OTC topical/inhalant nasal 
decongestant use as an ointment and steam inhalant. The data included a 
resubmission of three clinical studies (CRD 82-10, CRD 82-09, and CRD 
83-10), including a reanalysis of the data for study CRD 83-10 
submitted previously, to demonstrate the individual active ingredients 
as nasal decongestant topical/inhalant in a steam vaporizer. The 
submission also included two clinical effectiveness studies (CRD 87-25 
and CRD 89-01) on the combination of camphor, eucalyptus oil, and 
menthol for nasal decongestant use in an ointment. The comment 
requested that this combination be classified as a category I topical/
inhalant nasal decongestant in the same manner as previously done in 
the final monograph for OTC antitussive drug products (52 FR 30042 at 
30056).
    The agency has reviewed the data and other information (Ref. 20) 
and determined they are not sufficient to establish the effectiveness 
of the combination of camphor, eucalyptus oil, and menthol for nasal 
decongestant use in an ointment or for steam inhalation. The 
statistical reanalysis of study CRD 83-10 submitted to support the 
effectiveness of the individual active ingredients for nasal 
decongestant use was discussed in comment no. 5 in the final monograph 
for OTC nasal decongestant drug products (53 FR 43386 at 43389 to 
43390). The agency has determined that the conclusions reached on the 
single ingredients also apply to their use in combination. The latest 
submission contained no new information on this study. Further,

[[Page 78164]]

study CRD 83-10 was the only study involving use of the ingredients in 
a hot steam vaporizer. The agency had informed the author of the 
comment previously of the need to consider a repeated measurement 
analysis should another study be done (Ref. 21). That type of data has 
not been provided to date. Based on a lack of adequate clinical 
effectiveness data, the agency is not including this combination in 
this final monograph.

E. Comments on Specific Dosage Forms for OTC Cough-Cold Combination 
Drug Products

    (Comment 16) One comment requested that a combination of camphor, 
eucalyptus oil, and menthol be category I for antitussive use in a 
liquid dosage form by evaporation/inhalation at ambient temperatures. 
Noting the proposed category I status of the combination of camphor, 
eucalyptus oil, and menthol in an ointment dosage form for antitussive 
use (53 FR 30522 at 30547), the comment argued that inhalation of 
vapors by evaporation from a liquid at ambient temperature or from a 
topically applied ointment are comparable. The comment provided a 
protocol for an in vitro effectiveness study to determine whether the 
release of vapors from camphor, eucaplyptus oil, and menthol in a 
liquid dosage form by evaporation through a wick system is 
bioequivalent to the release of vapors from the same ingredients in an 
ointment dosage form rubbed on the chest (Ref. 22).
    The agency does not consider the release of vapors from a liquid 
dosage form by evaporation through a wick system to be comparable to 
the release of vapors from an ointment dosage form rubbed on the chest 
of the user. A liquid dosage form that remains in a stationary position 
and works by evaporation limits the mobility of the user to a specific 
distance from the container and, thus, is not comparable to the 
ointment dosage form. Because there are significant differences between 
the release of vapors from a wick system and the release of vapors from 
an ointment, the agency concludes that comparative in vitro studies 
will provide little useful information and that clinical studies are 
necessary to demonstrate effectiveness (Ref. 23).
    (Comment 17) One comment submitted data (Ref. 24) to support 
monograph status for the combination of 0.2 percent pheniramine maleate 
and 0.5 percent phenylephrine hydrochloride in a nasal spray dosage 
form when labeled for relief of nasal decongestion associated with 
colds, sinusitis, or allergic rhinitis. Two new clinical studies (WM 
440 and WM 464) were conducted to demonstrate added nasal decongestant 
benefit when 0.2 percent pheniramine maleate is added to a nasal spray 
containing 0.5 percent phenylephrine hydrochloride.
    Study WM 440 was a randomized, double-blind, multiple-dose, 
placebo-controlled, trial involving 90 subjects with seasonal allergic 
rhinitis. Subjects were given either 0.5 percent phenylephrine 
hydrochloride and 0.2 percent pheniramine maleate in combination, 0.5 
percent phenylephrine hydrochloride alone, or placebo two times daily, 
4 hours apart for 2 days. (Pheniramine maleate was not studied alone.) 
Total nasal air flow rates were measured prior to dosage and at timed 
intervals up to 8 hours. A subjective evaluation of symptoms associated 
with allergic rhinitis was also done at baseline and at hourly 
intervals. The investigator found significant carryover effects for 
time zero in the 2-day study and concluded that only results of day 1 
were significant and that the combination was more effective than 0.5 
percent phenylephrine hydrochloride alone.
    Study WM 464 was a double-blind, single-dose, randomized, parallel-
group, placebo-controlled, trial involving 240 subjects with upper 
respiratory tract infections (URTI). Subjective measurements of 
effectiveness were done at time intervals up to 4 hours using a ``100 
mm visual analog nasal congestion scale'' and a ``6 category nasal 
congestion relief rating scale.'' The investigator concluded the study 
showed that the combination drug product was more effective than either 
drug alone in subjects with URTI.
    The agency finds the data inadequate to support monograph status 
(Ref. 25). Study WM 440 is deficient because it did not include a group 
in which 0.2 percent pheniramine maleate was given as the active 
ingredient. In addition, there were significant carryover effects and, 
because only the results of the first day were useful, the duration of 
the study was insufficient. An adequate, randomized, parallel study in 
a sufficiently large number of subjects who receive the test drug(s) 
for at least 3 days (preferably for the duration of the syndrome) is 
required to demonstrate effectiveness of this combination.
    The agency does not consider study WM 464 adequate to demonstrate 
effectiveness because it was only a single-dose study and pheniramine 
maleate was not shown to be effective. For all the time/effectiveness 
measurement intervals up to 4 hours, pheniramine maleate alone showed 
an effect only at 15 minutes. The agency has determined that the 
dosages used in the study should have been administered according to 
the proposed label directions and the study should have had a duration 
of at least 3 days if the product is to be indicated for URTI and at 
least 7 days (preferably 2 weeks or more) if the product is to be 
indicated for allergies.
    The author of the comment submitted data to support a combination 
drug product consisting of both a nasal decongestant and an 
antihistamine, analyzed the study results for nasal decongestion and 
for symptoms associated with allergic rhinitis, but requested monograph 
status for this product only when labeled for relief of nasal 
congestion associated with colds, sinusitis, or allergic rhinitis. 
Nasal decongestant drug products can make this type of claim (Sec.  
341.80(b)). The comment did not indicate clearly what claim(s) were 
proposed for the pheniramine maleate component of this product. The 
agency concludes that data supporting claims for an oral antihistamine, 
such as relief of symptoms of runny nose and watery, itchy eyes, are 
necessary.
    (Comment 18) One comment requested that several proposed cough-cold 
combination formulations containing an oral nasal decongestant, oral 
antitussive, oral anesthetic/analgesic, and oral demulcent (53 FR 30522 
at 30537) not be limited to solid dosage forms. The comment stated 
that, from a pharmaceutical standpoint, it is possible to formulate 
safe and effective drug products that combine demulcents (e.g., 
gelatin, glycerin, and pectin) in liquid dosage forms with other cough-
cold monograph ingredients. The comment noted that the demulcent 
ingredients gelatin, glycerin, and pectin are permitted in lozenge or 
liquid dosage forms in the tentative final monograph for OTC oral 
health care drug products (53 FR 2436 at 2460 and 2461). The comment 
argued that the systemic action of cough-cold ingredients would not be 
adversely affected by the addition of a demulcent and that the 
demulcent would be applied directly to the throat tissues when 
swallowed, thus, producing the intended protective effect. The comment 
contended that it is both rational and practical for the final 
monograph to include combinations of systemically acting cough-cold 
ingredients and a demulcent in liquid dosage forms.
    The agency agrees with the comment. Nine combinations proposed in 
the tentative final monograph for OTC cough-cold combination drug 
products specify that the product be in a solid dosage form. See Sec.  
341.40(j), (p), (q), (u),

[[Page 78165]]

(v), (w), (x), (y), and (z). Menthol as a single ingredient in Sec.  
341.14(b)(2) is limited to a solid dosage form. However, menthol as an 
oral anesthetic/analgesic is not limited to solid dosage form products. 
If menthol were present in the above combinations as an oral 
anesthetic/analgesic ingredient, a liquid product would allow oral 
systemically acting cough-cold ingredients to be swallowed and would 
allow the oral anesthetic/analgesic (or demulcent, if present) to exert 
a topical therapeutic effect in the throat or mouth. The proposed 
directions for an anesthetic/analgesic or a demulcent in a liquid 
dosage form state that the product should be gargled, swished around in 
the mouth, or allowed to remain in place for at least 1 minute and then 
spit out (56 FR 48302 at 48343 to 48347). However, the anesthetic/
analgesic or demulcent in a combination product should not be spit out 
so that the systemically acting cough-cold ingredients can be 
effective. The agency does not see any safety problems when small 
quantities of an anesthetic/analgesic (menthol) or a demulcent 
(gelatin, glycerin, and pectin), as allowed in products regulated by 
OTC drug monographs, are swallowed. Therefore, the agency is allowing 
the nine combination drug products to be in either a liquid (to be 
swallowed) or a solid dosage form (to be dissolved in the mouth and 
swallowed), with specific directions for products with an anesthetic/
analgesic and/or a demulcent in a liquid dosage form in Sec.  
341.85(d)(1) of this final monograph.
    (Comment 19) One comment requested monograph status for the 
combination of camphor and menthol for steam inhalation antitussive 
use. The comment noted that in the tentative final monograph for OTC 
cough-cold combination drug products (53 FR 30522 at 30549) camphor and 
menthol individually are monograph drugs for steam inhalation use for 
antitussive claims (52 FR 30042, August 12, 1987); that further 
effectiveness data are not needed for these ingredients; and that data 
are needed to establish that the combination of these ingredients has 
some advantage over the single ingredients. The comment stated that 
whether camphor and menthol are delivered in a steam inhalation dosage 
form or an ointment dosage form, it is the inhalation of the aromatic 
ingredients that provides the antitussive benefits. The comment 
contended that steam inhalation provides a convenient dosage delivery 
form that is essentially identical to the ointment dosage form, which 
is rubbed on the chest, for consumers who want the benefits of 
medicated steam inhalation. The comment felt that the agency's 
``General Guidelines for OTC Drug Combination Products'' (Ref. 16) also 
support the combination by stating that patient acceptance or quality 
of formulation can be considered criteria to demonstrate the advantage 
of a combination over its single ingredients.
    The agency has determined that the comment did not provide 
sufficient information to demonstrate that the combination has some 
advantage over the single ingredients. As the agency stated in the 
tentative final monograph for OTC cough-cold combination drug products 
(53 FR 30522 at 30549), data are required to establish that the 
combination of camphor and menthol for steam inhalation antitussive use 
has some advantage over the single ingredients. A long marketing 
history and a belief that the combination of these ingredients may 
contribute to consumer acceptance of this drug product do not provide 
adequate data to demonstrate that the combination provides some 
advantage over the single ingredients. This combination for steam 
inhalation antitussive use is not included in the final monograph.

III. The Agency's Final Conclusions on OTC Cough-Cold Combination Drug 
Products

    Based on the available evidence, the agency is issuing a final 
monograph establishing conditions under which OTC cold, cough, allergy, 
bronchodilator, and antiasthmatic combination drug products are 
generally recognized as safe and effective and not misbranded. The 
agency has included 36 combinations in Sec. Sec.  341.40(a) through 
(bb) and 341.70(a) and (b) of the monograph. This includes the 
combination of an antihistamine, oral antitussive, and analgesic-
antipyretic, which was inadvertently not included in the proposal. All 
other cough-cold combination products are nonmonograph. These include, 
but are not limited to, the following combinations that were considered 
and rejected in this rulemaking: (1) Oral antitussive and debriding 
agent/oral wound cleanser; (2) antihistamine and debriding agent/oral 
wound cleanser; (3) oral antitussive and astringent; (4) antihistamine 
and astringent; (5) anticholinergic and expectorant; (6) antihistamine 
and expectorant; (7) antihistamine (if antihistamine is also a 
monograph antitussive, except diphenhydramine citrate and 
diphenhydramine hydrochloride) and oral antitussive; (8) oral 
antitussive (if antitussive is also a monograph antihistamine, except 
diphenhydramine citrate and diphenhydramine hydrochloride) and 
antihistamine; (9) antihistamine and anticholinergic; (10) 
antihistamine and oral anesthetic/analgesic; (11) antihistamine and 
oral demulcent; (12) antihistamine and nasal decongestant (administered 
topically as spray or drops); (13) oral antitussive and expectorant 
(for productive cough); (14) oral antitussive, expectorant, and oral 
nasal decongestant (for productive cough); (15) expectorant and oral 
anesthetic/analgesic; (16) expectorant and oral demulcent; (17) 
anticholinergic, antihistamine, and oral nasal decongestant; (18) 
atropine and oral nasal decongestant; (19) monograph ingredients from 
different pharmacologic groups if any ingredient is at less than the 
minimum effective dosage (unless the ingredient(s) are being used to 
treat the same symptom); (20) two or more ingredients at less than the 
minimum effective dosage and used to treat the same symptom (labeling 
claim) (even if the product contains monograph ingredients from 
different pharmacologic groups); (21) more than two active ingredients 
from the same pharmacologic group; (22) an antihistamine for the relief 
of symptoms of allergic rhinitis and an additional antihistamine which 
is added exclusively for sedation, and the product contains labeling 
which represents the additional antihistamine as a sleep-aid; (23) an 
antihistamine with a sleep-aid claim; (24) nonmonograph ingredients or 
labeling; (25) two monograph ingredients from the same pharmacologic 
group; (26) two monograph ingredients from the same pharmacologic group 
if either or both ingredients are at less than the minimum effective 
dosage; (27) a corrective (an active ingredient specifically intended 
to counteract a side effect of other ingredients in the product), e.g., 
caffeine, and any monograph ingredient(s); (28) phenobarbital (as a 
stimulant corrective); (29) several claimed active ingredients that are 
mixtures of volatile substances with overlapping pharmacologic 
activities for which a minimum effective dosage cannot be established 
for one or more of the ingredients when tested alone; (30) a stimulant, 
e.g., caffeine (at a fully effective level), and any monograph 
ingredient(s); (31) caffeine (15 to 30 mg) to combat lethargy (not as a 
sedative corrective) and cold preparations not containing 
antihistamines; (32) vitamin C and monograph ingredient(s) for 
prevention or treatment of the common cold; (33) any vitamins with 
labeling

[[Page 78166]]

claims for prevention or treatment of the common cold; (34) caffeine 
and ephedrine, phenylpropanolamine, or pseudoephedrine; (35) menthol, 
camphor, eucalyptus oil, thymol, cedar leaf oil, and nutmeg oil 
(myristica oil) in a suitable vehicle for steam inhalation or topical 
use as a nasal decongestant; (36) menthol and eucalyptus oil in a 
lozenge as a topical antitussive; and (37) menthol, camphor, eucalyptus 
oil, tincture of benzoin, and polyoxyethylene dodecanol for steam 
vaporizer use as an antitussive. A number of bronchodilator combination 
drug products were previously found nonmonograph (66 FR 49276).
    The agency has made a minor revision in the indication proposed in 
Sec.  341.85(b)(1) for combinations with an analgesic-antipyretic 
active ingredient labeled for relief of general cough-cold symptoms 
and/or the common cold, deleting the words ``muscular aches,'' 
``associated with,'' and ``(select one of the following: `the common 
cold' or `a cold').'' This deletion is consistent with recommendations 
made by the Nonprescription Drugs Advisory Committee and the OTC 
Analgesic Subcommittee of the Arthritis Advisory Committee on September 
8 and 9, 1994. The agency has concluded that labeling claims for 
analgesic-antipyretic ingredients (i.e., the myriad of claims in the 
labeling of presently marketed products and in proposed Sec.  
343.50(b)(1), (b)(2), and (b)(3)) should be simply and clearly stated 
in a general manner. The agency will be discussing this subject in more 
detail in the rulemaking for OTC internal analgesic-antipyretic drug 
products in a future issue of the Federal Register. If any changes 
subsequently occur in that rulemaking, the agency will amend the 
current final rule accordingly. The agency has also made minor 
revisions in the indications in Sec.  341.85(b)(1) and (b)(2) to put 
them into the new OTC drug product labeling format.
    When the tentative final monograph for cough-cold combination drug 
products was published in 1988, proposed Sec.  341.85(b)(4) referred to 
proposed Sec.  356.55(b)(1), which was proposed on January 27, 1988 (53 
FR 2436 at 2458). That section was renumbered as Sec.  356.52(b)(1) on 
September 24, 1991 (56 FR 48302 at 48343). Section 341.85(b)(4) in this 
final rule will be amended in the future to refer to Sec.  356.52(b), 
as appropriate.
    The agency has revised the warnings proposed in Sec.  341.85(c) to 
the new OTC drug labeling format, which has caused some changes in the 
way that the warning information is presented. In addition, in several 
instances, the agency changed a ``do not take for more than 10 days'' 
statement (internal analgesic component) to 7 days because of the 
antitussive or nasal decongestant component of the product, which has a 
7-day limit on use. This approach for warnings is similar to that used 
for directions when the time intervals for individual ingredients 
differ.
    Any drug product labeled, represented, or promoted for use as an 
OTC cough-cold combination drug that contains any of the ingredients 
listed in Sec.  310.545(a)(6) or that is not in conformance with the 
monograph (part 341) may be 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 (21 U.S.C. 352). Such a drug product cannot be 
marketed for OTC cough-cold use unless it is the subject of an approved 
application under section 505 of the act (21 U.S.C. 355) and part 314 
of the regulations (21 CFR part 314). An appropriate citizen petition 
to amend the monograph may also be submitted in accord with 21 CFR 
10.30 and 330.10(a)(12)(i). Any OTC cough-cold combination drug product 
initially introduced or initially delivered for introduction into 
interstate commerce after the effective date of this final rule that is 
not in compliance with the regulations is subject to regulatory action.

IV. Analysis of Impacts

    The agency did not receive any comments in response to its request 
in the tentative final monograph (53 FR 30522 at 30560) for specific 
comment on the economic impact of this rulemaking. FDA has examined the 
impacts of the final rule under Executive Order 12866 and the 
Regulatory Flexibility Act (5 U.S.C. 601-612) (as amended by subtitle D 
of the Small Business Regulatory Fairness Act of 1996 (Public Law 104-
121)), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). 
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). Under the Regulatory 
Flexibility Act, if a rule has a significant economic impact on a 
substantial number of small entities, an agency must analyze regulatory 
options that would minimize any significant impact of the rule on small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement of anticipated costs and 
benefits before proposing any rule that may result in an expenditure in 
any one year by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million (adjusted annually for 
inflation). The proposed rule published before the Unfunded Mandates 
Reform Act of 1995 was enacted.
    The agency concludes that this final rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
FDA has determined, as discussed in this section of the document, that 
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 Unfunded Mandates Reform Act of 1995 does not require FDA to 
prepare a statement of costs and benefits for the final rule, because 
the final rule is not expected to result in any 1-year expenditure that 
would exceed $100 million adjusted for inflation. The current inflation 
adjusted statutory threshold is about $110 million.
    The purpose of this final rule is to add 36 allowable combinations 
and their labeling to the monograph and to declare a number of other 
combinations as not generally recognized as safe and effective. Most of 
the individual cough-cold ingredients in these combination products are 
already included in the monograph, and the majority of marketed OTC 
cough-cold combination drug products already contain the ingredient 
combinations included in the final monograph. Most reformulations will 
involve the substitution of one cough-cold ingredient for another or 
the reformulation of a product containing a cough-cold ingredient and 
an oral health care ingredient, where such a combination has not been 
established as safe and effective.
    The agency's Drug Listing System identifies over 200 manufacturers 
and 300 marketers (distributors and repackers) of almost 8,300 OTC 
cough-cold combination drug products. Although some of these products 
may no longer be marketed, it is likely that there are additional 
marketers and products not currently included in the agency's system. 
Thus, FDA estimates that approximately 10,000 products could be subject 
to this final rule. Manufacturers will incur the vast majority of the 
incremental costs attributed to this rule.
    The agency is unable to determine the number of products that will 
require reformulation but, with few exceptions, manufacturers have 
known which ingredients were going to be included in

[[Page 78167]]

this final monograph for a substantial period of time. Many 
manufacturers have already reformulated their products. Others may 
decide to drop the nonmonograph products from their product lines, 
either because they already produce a substitute product that complies 
with the monograph, or because product sales are marginal and do not 
justify the expense of reformulation.
    The cost to reformulate a product will vary greatly depending on 
the nature of the change in formulation, the product, the process, and 
the size of the firm. Because of the large number of cough-cold 
ingredients available for substitution, no manufacturer should need to 
conduct clinical studies or change a dosage form; however, 
manufacturers will have to redo the validation (product, process, new 
supplier), conduct stability tests, and change master production 
records in order to ensure compliance with current good manufacturing 
practice. (See section 501(a)(1)(B) of the act (21 U.S.C. 351(a)(1)(B)) 
and 21 CFR parts 210 and 211.) The agency estimates that the cost of 
reformulation ranges from $100,000 to $500,000 per product, and may 
average about $250,000. FDA is uncertain about the number of cough-cold 
combination products that will be reformulated, but if 50 to 100 
products were reformulated, the total cost would range from $12.5 to 
$25 million. These costs may be smaller if most manufacturers elect to 
discontinue marketing marginal products rather than incur the expense 
of reformulating.
    The agency points out that the need to reformulate existing 
products has two components in this final rule. Ten of the monograph 
combinations contain analgesic-antipyretic active ingredients and nine 
other combinations contain oral health care (oral anesthetic/analgesic 
or demulcent) active ingredients. The monographs for the analgesic-
antipyretic and oral health care ingredients have not been finalized to 
date; therefore, the final rule does not require the reformulation of 
that component of such combinations. However, those specific 
combinations of cough-cold ingredient(s) with an analgesic-antipyretic 
or oral health care ingredient(s) that have been found unacceptable in 
this final rule must be reformulated (or removed from the market) by 
the date specified in the final rule. Consumers will benefit from 
reformulation because products that have not been found safe and 
effective will be replaced by products containing combinations of 
ingredients deemed safe and effective.
    Some relabeling is required by this final rule. However, most of 
the relabeling results from the earlier final rule on the standardized 
content and format requirements for all OTC drug products. (See the 
Federal Register of March 17, 1999, 63 FR 13254.) This final rule 
contains only a few labeling changes for combination products 
containing only cough-cold ingredients. Manufacturers will have 24 
months to relabel those products in the new OTC drug product labeling 
format in Sec.  201.66 (21 CFR 201.66).
    The incremental labeling costs for cough-cold combinations with an 
analgesic-antipyretic (proposed part 343) or oral health care active 
ingredient (proposed part 356) are minimal, because neither of those 
monographs has been completed to date. Although final monographs have 
not been published for OTC internal analgesic-antipyretic or oral 
health care drug products, the current final rule includes some 
specific labeling for cough-cold combination products that contain 
internal analgesic-antipyretic or oral health care active ingredients. 
The date for relabeling cough-cold combination drug products with those 
ingredients will be specified in those final monographs.
    The agency obtained estimates of relabeling costs for the type of 
changes required by this rule ranging from $2,700 to $10,000 per 
standard stock keeping unit (SKU) (individual products, packages, and 
sizes) for nationally branded products and from $500 to $1,500 per SKU 
for private label brands. Because nationally branded products make up 
only a small portion of all cough-cold combination products, FDA 
estimates, based on its experience, that 20 percent of the SKU's 
affected by this rule are branded products and 80 percent are private 
label products. Using the midpoints of the redesign cost ranges, the 
weighted average cost to relabel is $2,070 per SKU. Based on FDA 
estimates that 5 to 10 percent of the affected 10,000 SKU's will be 
relabeled, the total one-time incremental costs of relabeling would 
range from $1 to $2.1 million.
    The final rule will not require any new reporting or recordkeeping 
activities. Therefore, no additional professional skills are needed. 
There are no other Federal rules that duplicate, overlap, or conflict 
with the final rule. The agency concludes that there are no significant 
alternatives to the final rule that would adequately provide for the 
safe and effective use of OTC cough-cold combination drug products.
    The majority of the manufacturers, distributors, and repackers of 
cough-cold combination drug products subject to this final rule are 
considered small entities using the U.S. Small Business Administration 
(SBA) designations for this industry (750 employees). Because census 
size categories do not correspond to the SBA designation of 750 
employees, the agency figures are based on 500 employees. This final 
rule may have a significant impact on some small entities, especially 
those that need to reformulate or relabel a number of affected 
products. To provide assistance, FDA has taken steps to minimize the 
impact of relabeling costs on small entities. These steps include 
providing enough implementation time (24 months) to enable firms to use 
up existing labeling stock and to undertake the labeling changes 
required by this final monograph concurrently with the labeling changes 
required by the new OTC drug labeling format (Sec.  201.66). These 
actions will provide substantial flexibility and reduced regulatory 
burdens for small entities.
    The agency considered but rejected several labeling alternatives: 
(1) A shorter or longer implementation period, and (2) an exemption 
from coverage for small entities. While the agency believes that 
consumers would benefit from having this new labeling in place as soon 
as possible, the agency also acknowledges that coordinating the 
labeling changes in this final rule with implementation of the new OTC 
``Drug Facts'' labeling significantly reduces the costs of this final 
rule. Also, the 24-month compliance period will enable most 
manufacturers to implement the new labeling and to make the necessary 
manufacturing adjustments based on the seasonal nature of these cough-
cold combination drug products. The agency rejected an exemption for 
small entities because the new labeling and revised formulations, where 
applicable, are also needed by consumers who purchase products marketed 
by those entities.
    The agency has undertaken important steps to reduce the burden to 
small entities. Nevertheless, some entities, especially those firms 
that manufacture several affected products, may incur significant 
impacts. This economic analysis, together with other relevant sections 
of this document, serves as the agency's final regulatory flexibility 
analysis, as required under the Regulatory Flexibility Act.

V. Paperwork Reduction Act of 1995

    FDA concludes that the labeling requirements in this document are 
not subject to review by the Office of Management and Budget because 
they do not constitute a ``collection of information'' under the 
Paperwork

[[Page 78168]]

Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the labeling is 
a ``public disclosure of information originally supplied by the Federal 
government to the recipient for the purpose of disclosure to the 
public'' (5 CFR 1320.3(c)(2)).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

VIII. References

    The following references have been placed on display in the Dockets 
Management Branch (see ADDRESSES) under Docket No. 76N-052G and may be 
seen by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday.
    (1) Comment No. C00223.
    (2) Comment No. C00224.
    (3) Comment No. C00225.
    (4) Comment No. C00198.
    (5) Dick, E. C., S. L. Inhorn, and L. C. Jennings, ```Field' 
Trial Among Human Volunteers Mimicking a 7-Day Boarding School 
Environment,'' Comment No. C00198.
    (6) Letter from W. E. Gilbertson, FDA, to A. J. Iannarone, 
Hoffman-La Roche, Inc., coded LET105.
    (7) Letter from W. E. Gilbertson, FDA, to G. F. Hoffnagle, 
Richardson-Vicks, Inc., coded ANS1.
    (8) Letter from S. Salerno, The Procter & Gamble Co., to W. E. 
Gilbertson, FDA, dated July 6, 1995, in OTC Vol. 04GFM.
    (9) Letter from W. E. Gilbertson, FDA, to S. Salerno, The 
Procter & Gamble Co., dated July 27, 1995, in OTC Vol. 04GFM.
    (10) Attachment 4 in Comment No. C00218.
    (11) Attachment 6 in Comment No. C00218.
    (12) Attachment 8 in Comment No. C00218.
    (13) Attachment 10 in Comment No. C00218.
    (14) Attachment 11 in Comment No. C00218.
    (15) Letter from W. E. Gilbertson, FDA, to R. A. Stolt, The 
Procter & Gamble Co., coded LET118.
    (16) Food and Drug Administration ``General Guidelines for OTC 
Drug Combination Products, September 1978,'' Docket No. 78D-0322, 
Dockets Management Branch.
    (17) Comment No. C00111.
    (18) The United States Pharmacopeia XXI-The National Formulary 
XVI, The United States Pharmacopeial Convention, Inc., Rockville, 
MD, p. 1572, 1985.
    (19) Comment No. C00217.
    (20) Letter from W. E. Gilbertson, FDA, to R. A. Stolt, The 
Procter & Gamble Co., coded LET 117.
    (21) Letter from W. E. Gilbertson, FDA, to E. J. Hanus, 
Richardson-Vicks, coded LET095.
    (22) Comment No. C00191.
    (23) Letter from W. E. Gilbertson, FDA, to R. B. Seymour, 
O'Connor Pharmaceuticals, coded LET108.
    (24) Comment No. C00216.
    (25) Letter from W. E. Gilbertson, FDA, to J. R. Jacobs, 
Whitehall Laboratories, coded ANS2.

List of Subjects in 21 CFR Part 341

    Labeling, Over-the-counter drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
341 is amended as follows:

PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC 
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    1. The authority citation for 21 CFR part 341 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    2. Section 341.40 is added to subpart C to read as follows:


Sec.  341.40  Permitted combinations of active ingredients.

    The following combinations are permitted provided each active 
ingredient is present within the dosage limits established in parts 
341, 343, and 356 of this chapter and the product is labeled in 
accordance with Sec. Sec.  341.70 or 341.85:
    (a) Any single antihistamine active ingredient identified in Sec.  
341.12 may be combined with any generally recognized as safe and 
effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec.  341.85.
    (b) Any single antihistamine active ingredient identified in Sec.  
341.12 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a) provided that the product is 
labeled according to Sec.  341.85.
    (c) Any single antihistamine active ingredient identified in Sec.  
341.12 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a) and any generally recognized 
as safe and effective single analgesic-antipyretic active ingredient, 
or any combination of acetaminophen with other analgesic-antipyretic 
active ingredients, or any aspirin and antacid combination provided 
that the product is labeled according to Sec.  341.85.
    (d) Any single antihistamine active ingredient identified in Sec.  
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec.  
341.14(a)(1) through (a)(4) provided that the product is labeled 
according to Sec.  341.85(c)(4). Diphenhydramine citrate in Sec. Sec.  
341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in 
Sec. Sec.  341.12(g) and 341.14(a)(6) may be both the antihistamine and 
the antitussive active ingredient provided that the product is labeled 
according to Sec.  341.70(a).
    (e) Any single antihistamine active ingredient identified in Sec.  
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec.  
341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a) provided that the 
product is labeled according to Sec.  341.85(c)(4). Diphenhydramine 
citrate in Sec. Sec.  341.12(f) and 341.14(a)(5) or diphenhydramine 
hydrochloride in Sec. Sec.  341.12(g) and 341.14(a)(6) may be both the 
antihistamine and the antitussive active ingredient provided that the 
product is labeled according to Sec.  341.70(a).
    (f) Any single antihistamine active ingredient identified in Sec.  
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec.  
341.14(a)(1) through (a)(4) and any generally recognized as safe and 
effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec.  341.85(c)(4). Diphenhydramine 
citrate in Sec. Sec.  341.12(f) and 341.14(a)(5) or diphenhydramine 
hydrochloride in Sec. Sec.  341.12(g) and

[[Page 78169]]

341.14(a)(6) may be both the antihistamine and the antitussive active 
ingredient provided that the product is labeled according to Sec.  
341.70(a).
    (g) Any single antihistamine active ingredient identified in Sec.  
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec.  
341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a) and any generally 
recognized as safe and effective single analgesic-antipyretic active 
ingredient, or any combination of acetaminophen with other analgesic-
antipyretic active ingredients, or any aspirin and antacid combination 
provided that the product is labeled according to Sec.  341.85(c)(4). 
Diphenhydramine citrate in Sec. Sec.  341.12(f) and 341.14(a)(5) or 
diphenhydramine hydrochloride in Sec. Sec.  341.12(g) and 341.14(a)(6) 
may be both the antihistamine and the antitussive active ingredient 
provided that the product is labeled according to Sec.  341.70(a).
    (h) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a)(1) through (a)(4) may be combined with any single 
expectorant active ingredient identified in Sec.  341.18 provided that 
the product is labeled according to Sec.  341.85.
    (i) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a) may be combined with any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a) provided that the 
product is labeled according to Sec.  341.85.
    (j) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a)(1) through (a)(4) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec.  341.20(a) and 
any single expectorant active ingredient identified in Sec.  341.18 
provided that the product is labeled according to Sec.  341.85.
    (k) Any single antitussive active ingredient identified in Sec.  
341.14(a) or (b)(2) may be combined with any generally recognized as 
safe and effective single oral anesthetic/analgesic active ingredient, 
or any combination of anesthetic/analgesic active ingredients provided 
that the product is available in either a liquid (to be swallowed) or a 
solid dosage form (to be dissolved in the mouth and swallowed) and 
provided that the product is labeled according to Sec.  341.85. If the 
combination contains a topical antitussive, the product must be 
formulated in a solid dosage form to be dissolved in the mouth. Menthol 
in Sec.  341.14(b)(2) and part 356 of this chapter may be both the 
antitussive and the anesthetic/analgesic active ingredient provided 
that the product is labeled according to Sec.  341.70(b).
    (l) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a) may be combined with any generally recognized as safe 
and effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec.  341.85.
    (m) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a) may be combined with any single oral nasal decongestant 
active ingredient identified in Sec.  341.20(a) and any generally 
recognized as safe and effective single analgesic-antipyretic active 
ingredient, or any combination of acetaminophen with other analgesic-
antipyretic active ingredients, or any aspirin and antacid combination 
provided that the product is labeled according to Sec.  341.85.
    (n) Any single oral antitussive active ingredient identified in 
Sec.  341.14(a)(1) through (a)(4) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec.  341.20(a) and 
any single expectorant active ingredient identified in Sec.  341.18 and 
any generally recognized as safe and effective single analgesic-
antipyretic active ingredient, or any combination of acetaminophen with 
other analgesic-antipyretic active ingredients, or any aspirin and 
antacid combination provided that the product is labeled according to 
Sec.  341.85.
    (o) Any single expectorant active ingredient identified in Sec.  
341.18 may be combined with any generally recognized as safe and 
effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec.  341.85.
    (p) Any single expectorant active ingredient identified in Sec.  
341.18 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a) provided that the product is 
labeled according to Sec.  341.85.
    (q) Any single expectorant active ingredient identified in Sec.  
341.18 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec.  341.20(a) and any generally recognized 
as safe and effective single analgesic-antipyretic active ingredient, 
or any combination of acetaminophen with other analgesic-antipyretic 
active ingredients, or any aspirin and antacid combination provided 
that the product is labeled according to Sec.  341.85.
    (r) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a) may be combined with any generally recognized as 
safe and effective single analgesic-antipyretic active ingredient, or 
any combination of acetaminophen with other analgesic-antipyretic 
active ingredients, or any aspirin and antacid combination provided 
that the product is labeled according to Sec.  341.85.
    (s) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a) may be combined with any generally recognized as 
safe and effective single oral anesthetic/analgesic active ingredient 
identified, or any combination of anesthetic/analgesic active 
ingredients provided that the product is available in either a liquid 
(to be swallowed) or a solid dosage form (to be dissolved in the mouth 
and swallowed) and provided that the product is labeled according to 
Sec.  341.85.
    (t) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a) may be combined with any single antitussive active 
ingredient identified in Sec.  341.14(a) or (b)(2) and any generally 
recognized as safe and effective single oral anesthetic/analgesic 
active ingredient, or any combination of anesthetic/analgesic active 
ingredients provided that the product is available in either a liquid 
(to be swallowed) or a solid dosage form (to be dissolved in the mouth 
and swallowed) and provided that the product is labeled according to 
Sec.  341.85. If the combination contains a topical antitussive, the 
product must be formulated in a solid dosage form to be dissolved in 
the mouth.
    (u) Camphor identified in Sec.  341.14(b)(1) may be combined with 
menthol identified in Sec.  341.14(b)(2) and eucalyptus oil (1.2 to 1.3 
percent) provided that the product is available only in a suitable 
ointment vehicle and provided that the product is labeled according to 
Sec.  341.85.
    (v) Levmetamfetamine identified in Sec.  341.20(b)(1) may be 
combined with aromatics (camphor (54 milligrams (mg)), menthol (80 mg), 
methyl salicylate (11 mg), and lavender oil (4 mg)) provided that the 
product is available only as a nasal inhaler and provided that the 
product is labeled according to Sec.  341.85.
    (w) Any single antitussive active ingredient identified in Sec.  
341.14(a) or (b)(2) may be combined with any generally recognized as 
safe and effective single oral demulcent active ingredient provided 
that the product is available in either a liquid (to be swallowed) or a 
solid dosage form (to be dissolved in the mouth and swallowed) and 
provided that the product is labeled according to Sec.  341.85. If the 
combination contains a topical

[[Page 78170]]

antitussive, the product must be formulated in a solid dosage form to 
be dissolved in the mouth.
    (x) Any single oral nasal decongestant active ingredient identified 
in Sec.  341.20(a) may be combined with any generally recognized as 
safe and effective single oral demulcent active ingredient provided 
that the product is available in either a liquid (to be swallowed) or a 
solid dosage form (to be dissolved in the mouth and swallowed) and 
provided that the product is labeled according to Sec.  341.85.
    (y) Any single antitussive active ingredient identified in Sec.  
341.14(a) or (b)(2) may be combined with any single oral nasal 
decongestant active ingredient identified in Sec.  341.20(a) and any 
generally recognized as safe and effective single oral demulcent active 
ingredient provided that the product is available in either a liquid 
(to be swallowed) or a solid dosage form (to be dissolved in the mouth 
and swallowed) and provided that the product is labeled according to 
Sec.  341.85. If the combination contains a topical antitussive, the 
product must be formulated in a solid dosage form to be dissolved in 
the mouth.
    (z) Any single antitussive active ingredient identified in Sec.  
341.14(a) or (b)(2) may be combined with any generally recognized as 
safe and effective single oral anesthetic/analgesic active ingredient 
or any combination of anesthetic/analgesic active ingredients and any 
generally recognized as safe and effective single oral demulcent active 
ingredient provided that the product is available in either a liquid 
(to be swallowed) or a solid dosage form (to be dissolved in the mouth 
and swallowed) and provided that the product is labeled according to 
Sec.  341.85. If the combination contains a topical antitussive, the 
product must be formulated in a solid dosage form to be dissolved in 
the mouth.
    (aa) Any single oral nasal decongestant active ingredient 
identified in Sec.  341.20(a) may be combined with any generally 
recognized as safe and effective single oral anesthetic/analgesic 
active ingredient or any combination of oral anesthetic/analgesic 
active ingredients and any generally recognized as safe and effective 
single oral demulcent active ingredient provided that the product is 
available in either a liquid (to be swallowed) or a solid dosage form 
(to be dissolved in the mouth and swallowed) and provided that the 
product is labeled according to Sec.  341.85.
    (bb) Any single antitussive active ingredient identified in Sec.  
341.14(a) or (b)(2) may be combined with any single oral nasal 
decongestant active ingredient identified in Sec.  341.20(a) and any 
generally recognized as safe and effective single oral anesthetic/
analgesic active ingredient identified or any combination of 
anesthetic/analgesic active ingredients and any generally recognized as 
safe and effective single oral demulcent active ingredient provided 
that the product is available in either a liquid (to be swallowed) or a 
solid dosage form (to be dissolved in the mouth and swallowed) and 
provided that the product is labeled according to Sec.  341.85. If the 
combination contains a topical antitussive, the product must be 
formulated in a solid dosage form to be dissolved in the mouth.
    3. Section 341.70 is amended by adding paragraph (b) to read as 
follows:


Sec.  341.70  Labeling of OTC drug products containing ingredients that 
are used for treating concurrent symptoms (in either a single-
ingredient or combination drug product).

* * * * *
    (b) For products containing menthol identified in Sec. Sec.  
341.14(b)(2) and 356.12(f) of this chapter. The product contains 5 to 
10 milligrams menthol. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as a 
``cough suppressant/oral anesthetic'' or ``antitussive (cough 
suppressant)/oral anesthetic.'' The indications shall be combined from 
Sec.  341.74(b) and part 356 of this chapter. The warnings shall be 
combined from Sec.  341.74(c)(1), (c)(2), and (c)(3) and part 356 of 
this chapter. The directions shall be: ``Directions [in bold type] 
[bullet]\1\ adults and children 2 years and over: dissolve lozenge 
slowly in the mouth. Repeat every hour as needed or as directed by a 
doctor. [bullet] children under 2 years of age: ask a doctor''.
---------------------------------------------------------------------------

    \1\See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
---------------------------------------------------------------------------

    4. Section 341.85 is added to subpart C to read as follows:


Sec.  341.85  Labeling of permitted combinations of active ingredients.

    The statements of identity, indications, warnings, and directions 
for use, respectively, applicable to each ingredient in the product may 
be combined to eliminate duplicative words or phrases so that the 
resulting information is clear and understandable.
    (a) Statement of identity. For a combination drug product that has 
an established name, the labeling of the product states the established 
name of the combination drug product, followed by the statement of 
identity for each ingredient in the combination, as established in the 
statement of identity sections of the applicable OTC drug monographs. 
If there is no established name, the labeling of the product states the 
statement of identity for each ingredient in the combination, as 
established in the statement of identity sections of the applicable OTC 
drug monographs, unless otherwise stated in this paragraph (a).
    (1) For permitted combinations identified in Sec.  341.40(a), (c), 
(f), (g), (l), (m), (n), (o), (q), and (r) containing an analgesic-
antipyretic active ingredient. The analgesic-antipyretic component of 
the product shall be identified as a ``pain reliever'' or ``analgesic 
(pain reliever).'' If the product is also labeled to relieve fever, 
then the analgesic-antipyretic component is identified as a ``pain 
reliever-fever reducer'' or ``analgesic (pain reliever)-antipyretic 
(fever reducer).''
    (2) [Reserved]
    (b) Indications. The labeling of the product states, under the 
heading ``Uses,'' the indication(s) for each ingredient in the 
combination, as established in the indications sections of the 
applicable OTC drug monographs, unless otherwise stated in this 
paragraph (b). Other truthful and nonmisleading statements, describing 
only the indications for use that have been established and listed in 
the applicable OTC drug monographs or listed in this paragraph (b), 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) For permitted combinations containing an analgesic-antipyretic 
active ingredient identified in Sec.  341.40(a), (c), (f). (g), (l), 
(m), (n), (o), (q), and (r) when labeled for relief of general cough-
cold symptoms and/or the common cold.
    (i) The labeling for the analgesic-antipyretic ingredients states 
``[bullet] temporarily relieves [bullet] minor aches and pains [bullet] 
headache'' and ``[bullet] temporarily reduces fever''.
    (ii) The labeling for the cough-cold ingredient(s) may follow a 
separate bullet(s) or may be combined with the relieves part of the 
indication in paragraph (b)(1)(i) of this section.
    (2) For permitted combinations containing an analgesic-antipyretic 
active ingredient identified in Sec.  341.40(a), (c), (f), (g), (m), 
(q), and (r) when labeled for relief of hay fever/

[[Page 78171]]

allergic rhinitis and/or sinusitis symptoms.
    (i) The labeling for the analgesic-antipyretic ingredients states 
``[bullet] temporarily relieves [bullet] minor aches and pains [bullet] 
headache''.
    (ii) The indication(s) for the cough-cold ingredient(s) consists of 
the labeling for antihistamines in Sec.  341.72(b)(1) or (b)(2) and/or 
nasal decongestants in Sec.  341.80(b)(1)(ii) and/or (b)(1)(iii), as 
appropriate, and the labeling for any other cough-cold ingredient 
present in the combination. This labeling may follow a separate 
bullet(s) or may be combined with the indication in paragraph (b)(2)(i) 
of this section.
    (3) For permitted combinations containing an oral analgesic-
antipyretic active ingredient identified in Sec.  341.40(a), (c), (f), 
(g), (m), (q), and (r) when labeled for relief of general cough-cold 
symptoms and/or the common cold and for relief of hay fever/allergic 
rhinitis and/or sinusitis symptoms. The labeling states both 
indications in paragraphs (b)(1) and (b)(2) of this section.
    (4) For permitted combinations containing an oral anesthetic-
analgesic active ingredient identified in Sec.  341.40(k), (s), (t), 
(z), (aa), and (bb). The labeling for the anesthetic-analgesic 
ingredients in part 356 of this chapter should be used.
    (5) For permitted combinations containing camphor, menthol, and 
eucalyptus oil identified in Sec.  341.40(u). The labeling for 
antitussive ingredients in Sec.  341.74(b) should be used.
    (6) For permitted combinations containing levmetamfetamine with 
aromatics identified in Sec.  341.40(v). The labeling for nasal 
decongestant ingredients in Sec.  341.80(b) should be used.
    (7) Other allowable statements. In addition to the required 
information identified in paragraph (b) of this section, the labeling 
of the combination drug product may contain any of the ``other 
allowable statements'' (if any), that are identified in the applicable 
OTC drug monographs, provided such statements are neither placed in 
direct conjunction with information required to appear in the labeling 
nor occupy labeling space with greater prominence or conspicuousness 
than the required information.
    (c) Warnings. The labeling of the product states, under the heading 
``Warnings,'' the warning(s) for each ingredient in the combination, as 
established in the warnings sections of the applicable OTC drug 
monographs, unless otherwise stated in paragraph (c) of this section.
    (1) For permitted combinations containing an antitussive and an 
analgesic-antipyretic identified in Sec.  341.40(f), (g), (l), and (m). 
The labeling states the following warnings:
    (i) For products labeled only for adults. The following warning 
should be used instead of the warnings in Sec.  341.74(c)(1) and part 
343 of this chapter: ``Stop use and ask a doctor if [in bold type] 
[bullet] pain or cough gets worse or lasts more than 7 days [bullet] 
fever gets worse or lasts more than 3 days [bullet] redness or swelling 
is present [bullet] new symptoms occur [bullet] cough comes back or 
occurs with rash or headache that lasts. These could be signs of a 
serious condition.''
    (ii) For products labeled only for children under 12 years of age. 
The following warning should be used instead of the warnings in Sec.  
341.74(c)(3) and part 343 of this chapter: ``Stop use and ask a doctor 
if [in bold type] [bullet] pain or cough gets worse or lasts more than 
5 days [bullet] fever gets worse or lasts more than 3 days [bullet] 
redness or swelling is present [bullet] new symptoms occur [bullet] 
cough comes back or occurs with rash or headache that lasts. These 
could be signs of a serious condition.''
    (iii) For products labeled for both adults and for children under 
12 years of age. The following warning should be used instead of the 
warnings in Sec.  341.74(c)(2) and part 343 of this chapter: ``Stop use 
and ask a doctor if [in bold type] [bullet] pain or cough gets worse or 
lasts more than 5 days (children) or 7 days (adults) [bullet] fever 
gets worse or lasts more than 3 days [bullet] redness or swelling is 
present [bullet] new symptoms occur [bullet] cough comes back or occurs 
with rash or headache that lasts. These could be signs of a serious 
condition.''
    (2) For permitted combinations containing an expectorant and an 
analgesic-antipyretic identified in Sec.  341.40(o). The labeling 
states the following warnings:
    (i) For products labeled only for adults. The warning in paragraph 
(c)(1)(i) of this section should be used instead of the warnings in 
Sec.  341.78(c)(3) and part 343 of this chapter.
    (ii) For products labeled only for children under 12 years of age. 
The warning in paragraph (c)(1)(ii) of this section should be used 
instead of the warnings in Sec.  341.78(c)(3) and part 343 of this 
chapter.
    (iii) For products labeled for both adults and for children under 
12 years of age. The warning in paragraph (c)(1)(iii) of this section 
should be used instead of the warnings in Sec.  341.78(c)(3) and part 
343 of this chapter.
    (3) For permitted combinations containing a nasal decongestant and 
an analgesic-antipyretic identified in Sec.  341.40(c), (g), (m), (n), 
(q), and (r). The labeling states the following warnings:
    (i) For products labeled only for adults. The following warning 
should be used instead of the warnings in Sec.  341.80(c)(1)(i)(B) and 
part 343 of this chapter: ``Stop use and ask a doctor if [in bold type] 
[bullet] pain or nasal congestion gets worse or lasts more than 7 days 
[bullet] fever gets worse or lasts more than 3 days [bullet] redness or 
swelling is present [bullet] new symptoms occur''.
    (ii) For products labeled for only children under 12 years of age. 
The following warning should be used instead of the warnings in Sec.  
341.80(c)(1)(ii)(B) and part 343 of this chapter: ``Stop use and ask a 
doctor if [in bold type] [bullet] pain or nasal congestion gets worse 
or lasts more than 5 days [bullet] fever gets worse or lasts more than 
3 days [bullet] redness or swelling is present [bullet] new symptoms 
occur''.
    (iii) For products labeled for both adults and children under 12 
years of age. The following warning should be used instead of the 
warnings in Sec.  341.80(c)(1)(iii) and part 343 of this chapter: 
``Stop use and ask a doctor if [in bold type] [bullet] pain or nasal 
congestion gets worse or lasts more than 5 days (children) or 7 days 
(adults) [bullet] fever gets worse or lasts more than 3 days [bullet] 
redness or swelling is present [bullet] new symptoms occur''.
    (4) For permitted combinations containing an antihistamine combined 
with an oral antitussive. The labeling states the warning ``When using 
this product [in bold type] [bullet] may cause marked drowsiness.'' The 
word ``marked'' may be deleted from the warning upon petition under the 
provisions of Sec.  10.30 of this chapter provided adequate data are 
submitted to demonstrate that the combination product does not cause a 
significant increase in drowsiness as compared with each active 
ingredient when tested alone. The petition and the data it contains 
will be maintained in a permanent file for public review in the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852.
    (5) For permitted combinations containing camphor, menthol, and 
eucalyptus oil identified in Sec.  341.40(u). The labeling states the 
warnings for topical antitussive ingredients in Sec.  341.74(c).

[[Page 78172]]

    (6) For permitted combinations containing levmetamfetamine with 
aromatics identified in Sec.  341.40(v). The labeling states the 
warnings for topical nasal decongestant ingredients in Sec.  
341.80(c)(2).
    (d) Directions. The labeling of the product states, under the 
heading ``Directions,'' directions that conform to the directions 
established for each ingredient in the directions sections of the 
applicable OTC drug monographs, unless otherwise stated in paragraph 
(d) of this section. When the time intervals or age limitations for 
administration of the individual ingredients differ, the directions for 
the combination product may not exceed any maximum dosage limits 
established for the individual ingredients in the applicable OTC drug 
monograph.
    (1) For permitted combinations containing an anesthetic/analgesic 
and/or a demulcent in a liquid dosage form identified in Sec.  
341.40(k), (s), (t), (w), (x), (y), (z), (aa), and (bb). The labeling 
states ``[optional, bullet] gargle, swish around, or keep in the mouth 
for at least 1 minute and then swallow. Do not spit out.''
    (2) For permitted combinations containing camphor, menthol, and 
eucalyptus oil identified in Sec.  341.40(u). The labeling states the 
directions for topical antitussive ingredients in Sec.  341.74(d).
    (3) For permitted combinations containing levmetamfetamine with 
aromatics identified in Sec.  341.40(v). The labeling states the 
directions for topical nasal decongestant ingredients in Sec.  
341.80(d)(2)(i) and (d)(2)(viii).

    Dated: August 20, 2002.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 02-32158 Filed 12-20-02; 8:45 am]
BILLING CODE 4160-01-S