[Federal Register Volume 60, Number 36 (Thursday, February 23, 1995)]
[Proposed Rules]
[Pages 10286-10293]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4464]




[[Page 10285]]

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Part VI





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 341



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

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 341

[Docket No. 76N-052G]
RIN 0905-AA06


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the tentative final monograph for over-the-counter (OTC) cold, cough, 
allergy, bronchodilator, and antiasthmatic combination drug products to 
classify combination drug products containing the ingredients 
diphenhydramine citrate or diphenhydramine hydrochloride. The agency 
recently amended the final monograph for OTC antitussive drug products 
(products used to relieve cough) to include the ingredients 
diphenhydramine citrate and diphenhydramine hydrochloride. The agency 
also previously included diphenhydramine citrate and diphenhydramine 
hydrochloride in the final monograph for OTC antihistamine drug 
products. This proposal is part of the ongoing review of OTC drug 
products conducted by FDA.

DATES: Written comments or objections by May 9, 1995; written comments 
on the agency's economic impact determination by May 9, 1995.

ADDRESSES: Written comments or objections to the Dockets Management 
Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 
Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-810), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 9, 1976 (41 FR 38312), FDA 
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance 
notice of proposed rulemaking to establish a monograph for OTC cold, 
cough, allergy, bronchodilator, and antiasthmatic drug products. In 
that notice, the Advisory Review Panel on OTC Cold, Cough, Allergy, 
Bronchodilator, and Antiasthmatic Drug Products (the Panel) discussed 
OTC cough-cold combination drug products, including combinations 
containing an oral antitussive and/or an antihistamine (41 FR 38312 at 
38327). The Panel considered combinations containing the ingredient 
diphenhydramine hydrochloride. (Diphenhydramine citrate was not 
submitted for the Panel's consideration.) The Panel recommended that 
diphenhydramine hydrochloride be Category I (generally recognized as 
safe and effective) as both an oral antitussive and an antihistamine. 
However, the Panel recommended a Category II classification (not 
generally recognized as safe and effective or misbranded) for any 
combination containing an oral antitussive ingredient and an 
antihistamine if the antitussive ingredient is also a Category I 
antihistamine or if the antihistamine is also a Category I antitussive. 
Diphenhydramine hydrochloride was the only ingredient that the Panel 
classified in Category I for both antitussive and antihistamine use.
    In the Federal Register of August 12, 1988 (53 FR 30522), FDA 
published the tentative final monograph for OTC cold, cough, allergy, 
bronchodilator, and antiasthmatic combination drug products. FDA did 
not include specific combinations for OTC cough-cold drug products 
containing diphenhydramine citrate or diphenhydramine hydrochloride for 
OTC oral antitussive use in that tentative final monograph. At that 
time, these ingredients were not included in the final monograph for 
OTC antitussive drug products because adequate data to support 
monograph status were not publicly available. Subsequently, data were 
submitted to the rulemaking for OTC antitussive drug products (see 
discussion below).
    In the tentative final monograph, the agency discussed combinations 
containing a drug recognized as both an antitussive and an 
antihistamine combined with another oral antitussive and/or 
antihistamine (53 FR 30522 at 30539). The agency proposed that such 
combinations be Category III (available data are insufficient to 
classify as safe and effective, and further testing is required).
    In the Federal Register of December 9, 1992 (57 FR 58378), the 
agency proposed that diphenhydramine citrate and diphenhydramine 
hydrochloride be included in the final monograph for OTC antitussive 
drug products as single ingredients. This action was taken because the 
data needed to support monograph status had been made publicly 
available. The proposal was recently finalized in the Federal Register 
of June 3, 1994 (59 FR 29172). In that final rule, the agency stated 
that it would address the following matters in a future issue of the 
Federal Register: (1) OTC cough-cold combination drug products 
containing diphenhydramine citrate or diphenhydramine hydrochloride for 
antitussive use, (2) concurrent antitussive and antihistamine use of 
diphenhydramine ingredients (either in an OTC cough-cold single-
ingredient or combination drug product) for concurrent symptoms, and 
(3) ``multiuse'' labeling for OTC drug products containing an 
ingredient that may be used separately for more than one indication for 
nonconcurrent symptoms--with full, separate labeling for each 
indication. The first two subjects are addressed in this proposed rule. 
The third will be addressed in a future issue of the Federal Register. 
Labeling issues relating to that topic are broader than 
diphenhydramine, applying to other OTC drug ingredients that have more 
than one pharmacologic activity and that are included or proposed for 
inclusion in more than one OTC drug monograph. For example, sodium 
bicarbonate has a number of drug uses.

II. The Agency's Proposals for OTC Cough-Cold Combination Drug 
Products Containing Diphenhydramine Citrate or Diphenhydramine 
Hydrochloride for Antitussive Use

    In this proposed rule, the agency has considered all OTC cough-cold 
combination products classified in the tentative final monograph for 
OTC cough-cold combination drug products (53 FR 30522) that could 
include diphenhydramine as an oral antitussive or as an antihistamine. 
The agency is proposing only a few changes in the classification of 
these combinations when diphenhydramine is included in the combination 
as an antitussive or an antihistamine (see section III). The following 
table lists the combinations that were considered:

                                                                                                                
[[Page 10287]]                                                                                                  
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                                 Table 1                                
-------------------------------------------------------------------------
Cough-Cold Combinations Considered in the Tentative Final Monograph That
               Contain an Antihistamine or an Antitussive               
-------------------------------------------------------------------------
A. Combinations containing an oral antitussive, but not an antihistamine
                                                                        
      1. Analgesic-antipyretic(s) and oral antitussive                  
      2. Analgesic-antipyretic(s) and oral antitussive and oral nasal   
       decongestant                                                     
      3. Oral antitussive and expectorant (if labeled for nonproductive 
       cough)                                                           
      4. Oral antitussive and oral nasal decongestant                   
      5. Oral antitussive and expectorant and oral nasal decongestant   
       (if labeled for nonproductive cough)                             
      6. Oral antitussive and anesthetic/analgesic (if available only in
       a solid dosage form)                                             
      7. Oral nasal decongestant and oral antitussive and anesthetic/   
       analgesic (if available only in a solid dosage form)             
      8. Oral antitussive and oral demulcent (if available in a solid   
       dosage form)                                                     
      9. Oral nasal decongestant and oral antitussive and oral demulcent
       (if available only in a solid dosage form)                       
      10. Oral antitussive and anesthetic/analgesic and oral demulcent  
       (if available only in a solid dosage form)                       
      11. Oral nasal decongestant and oral antitussive and anesthetic/  
       analgesic and oral demulcent (if available only in a solid dosage
       form)                                                            
      12. Oral antitussive and debriding agent/oral wound cleanser      
      13. Oral antitussive and astringent                               
      14. Oral bronchodilator and oral antitussive (if labeled for cough
       associated with asthma)                                          
      15. Oral antitussive and bronchodilator used as an antitussive (if
       labeled for productive cough)                                    
      16. Oral antitussive and expectorant (if labeled for productive   
       cough)                                                           
      17. Oral antitussive and expectorant and oral nasal decongestant  
       (if labeled for productive cough)                                
      18. Analgesic-antipyretic(s) and oral antitussive and expectorant 
       and oral nasal decongestant                                      
                                                                        
B. Combinations containing an antihistamine, but not an oral            
 antitussive.                                                           
                                                                        
      1. Analgesic-antipyretic(s) and antihistamine                     
      2. Analgesic-antipyretic(s) and antihistamine and oral nasal      
       decongestant                                                     
      3. Antihistamine and oral nasal decongestant                      
      4. Antihistamine and debriding agent/oral wound cleanser          
      5. Antihistamine and astringent                                   
      6. Antihistamine and expectorant                                  
      7. Oral bronchodilator and antihistamine                          
      8. Antihistamine and anticholinergic                              
      9. Anticholinergic and antihistamine and oral nasal decongestant  
      10. Combinations containing an antihistamine for the relief of    
       symptoms of allergic rhinitis and an additional antihistamine    
       which is added exclusively for sedation, and the product contains
       labeling which represents the additional antihistamine as a sleep-
       aid                                                              
      11. Combinations containing an antihistamine with a sleep- aid    
       claim                                                            
      12. Antihistamine and oral anesthetic/analgesic                   
      13. Antihistamine and oral demulcent                              
      14. Antihistamine and nasal decongestant (administered topically  
       as spray or drops)                                               
                                                                        
C. Combinations containing both an oral antitussive and an              
 antihistamine.                                                         
                                                                        
      1. Antihistamine and oral antitussive (if labeled ``May cause     
       marked drowsiness'')                                             
      2. Analgesic-antipyretic(s) and oral antitussive and oral nasal   
       decongestant and antihistamine                                   
      3. Antihistamine and oral antitussive and oral nasal decongestant 
      4. Antihistamine (if antihistamine is also a Category I           
       antitussive) and oral antitussive                                
      5. Oral antitussive (if antitussive is also a Category I          
       antihistamine) and antihistamine                                 
------------------------------------------------------------------------

A. OTC cough-cold combinations containing: (1) An oral antitussive, but 
no antihistamine and (2) an antihistamine, but no antitussive.

1. Comparison of Category I Antitussive Combinations With Category II 
and III Antihistamine-containing Combinations.
    The agency has compared all of the Category I combinations 
containing an oral antitussive, but not an antihistamine (in Table 1, 
A.1. through A.11.), with all of the Category II and III combinations 
containing an antihistamine, but not an oral antitussive (in Table 1, 
B.4. through B.14.). The agency compared the classes of ingredients 
included with an oral antitussive in Category I and the classes 
included with an antihistamine in Categories II and III to determine 
which combinations similar to the Category II and III antihistamine 
combinations were included in the Category I antitussive combinations. 
The following table lists these combinations:

                                                                        
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                                 Table 2                                
-------------------------------------------------------------------------
     Category I Oral Antitussive       Corresponding Category II or III 
             Combination                   Antihistamine Combination    
------------------------------------------------------------------------
Oral antitussive and an expectorant   Antihistamine and expectorant     
Oral antitussive and an expectorant   None                              
 and a nasal decongestant (if                                           
 labeled for nonproductive cough)                                       
Oral antitussive and an anestehetic/  Antihistamine and an anesthetic/  
 analgesic in a solid dosage form      analgesic in a solid dosage form 
Oral antitussive and an demulcent in  Antihistamine and a demulcent     
 a solid dosage form                                                    
Oral nasal decongestant and an oral   None                              
 antitussive and an anesthetic/                                         
 analgesic in a solid dosage form                                       
Oral nasal decongestant and an oral   None                              
 antitussive and a demulcent in                                         
 solid dosage                                                           
------------------------------------------------------------------------

    [[Page 10288]] (a) Combination drug products containing an 
expectorant and an oral antitussive that is also an antihistamine. The 
Panel recommended a Category I classification for combinations 
containing an oral antitussive and an expectorant that is labeled for 
nonproductive cough (41 FR 38312 at 38328). The agency concurred in the 
tentative final monograph for OTC cough-cold combination drug products 
(53 FR 30522 at 30556). However, the Panel recommended a Category II 
classification for combinations containing an antihistamine and an 
expectorant. In this combination, the anticholinergic effect (drying 
action) of the antihistamine would produce the opposite effect of the 
secretory action of the expectorant ingredient. Thus, the combination 
would be medically irrational (41 FR 38312 at 38326). The agency 
concurred with the Panel in the OTC cough-cold combinations tentative 
final monograph (53 FR 30522 at 30556). Because diphenhydramine is an 
antihistamine as well as an antitussive, it would have anticholinergic 
effects whether it is included in a combination as an oral antitussive 
or as an antihistamine. Accordingly, the agency is proposing a Category 
II classification for all combinations containing an expectorant and an 
oral antitussive if the antitussive is also an antihistamine. The 
agency is revising proposed Sec. 341.40(g) and (i) to replace the 
phrase ``Any single oral antitussive active ingredient identified in 
Sec. 341.14(a) * * *'' with the phrase ``Any single oral antitussive 
active ingredient identified in Sec. 341.14(a)(1) through (a)(4) * * 
*.'' This revision specifically excludes combinations containing 
diphenhydramine citrate or diphenhydramine hydrochloride as an 
antitussive.
    (b) Combination drug products containing an anesthetic/analgesic 
and/or a demulcent (in a solid dosage form) and an oral antitussive 
that is also an antihistamine. The Cough-Cold Panel reviewed data 
relating to combination drug products containing cough-cold and oral 
health care active ingredients with claims for relief of sore throat 
(41 FR 38312 at 38325). The Panel established specific criteria for the 
treatment of symptoms with combination products and based its Category 
I recommendations on whether the combination is rational concurrent 
therapy for a significant and existing population. The Panel determined 
that products containing an antitussive or a nasal decongestant 
combined with an oral anesthetic/analgesic in a lozenge dosage form are 
rational and recommended a Category I classification for these 
combinations. The agency concurred with the Panel in the tentative 
final monograph for OTC cough-cold combination drug products. However, 
the agency determined that such a combination could be rational only if 
the combination drug product were in a solid dosage form so that the 
anesthetic/analgesic ingredient or the demulcent ingredient may exert 
its topical effect and the antitussive can be ingested (53 FR 30522 at 
30536 and 30537).
    The Panel did not discuss combinations containing an antihistamine 
with an anesthetic/analgesic or a demulcent. However, the agency 
considered such combinations in the OTC cough-cold combinations 
tentative final monograph (53 FR 30522 at 30537). The agency stated 
that the combination of an antihistamine and an oral anesthetic/
analgesic or an oral demulcent could be rational if the combination 
drug product is in a solid dosage form. In addition, the symptoms of 
allergic rhinitis and minor throat irritation that may result from the 
nasal congestion that often occurs with allergic rhinitis and 
subsequent breathing through the mouth could be treated concurrently 
with such combinations. However, the agency also stated that it was 
unaware of any currently marketed drug product that contains such a 
combination and that no data were submitted to demonstrate a 
significant target population with concurrent symptoms that would 
benefit from such a combination. Therefore, the agency proposed a 
Category III classification for the combination of an antihistamine 
with an oral anesthetic/analgesic or an oral demulcent. The agency has 
since determined that data do exist to support a target population for 
such combinations based on epidemiological data accepted by the Panel 
(41 FR 38312 at 38325). The agency believes that a Category I 
classification is appropriate for combinations containing an oral 
antitussive (which is also an antihistamine, although antihistamine 
claims cannot be made for these combinations) with an oral anesthetic/
analgesic or an oral demulcent if in a solid dosage form. Thus, the 
agency is proposing to include diphenhydramine citrate and 
diphenhydramine hydrochloride in combinations specified in 
Sec. 341.40(j), (q), (u), (w), (x), and (z). At this time, sufficient 
data have not been provided to support a suitable target population 
with concurrent symptoms of sufficient duration to justify an 
antihistamine claim for any of these combination drug products. 
Therefore, any of these combinations that contain diphenhydramine 
citrate or diphenhydramine hydrochloride as the antitussive cannot also 
make antihistamine claims.
2. Category II and III Combinations Containing an Antitussive.
    The agency has considered all OTC cough-cold combinations 
containing an oral antitussive, but no antihistamine, that were placed 
in Category II or III in the OTC cough-cold combinations tentative 
final monograph (combinations in Table 1 under A.1. through A.18.). The 
agency has determined that these combinations would be categorized in 
the same manner if diphenhydramine were used as the antitussive. The 
agency is not aware of any data or information that would support 
reclassification of any of these combinations because they contain 
diphenhydramine rather than any other monograph oral antitussive 
ingredient.
3. Combinations Containing an Antihistamine With no Corresponding 
Category I Antitussive Combination.
    The agency considered all antihistamine combinations (not including 
an oral antitussive) that did not have a corresponding Category I 
antitussive combination (not including an antihistamine), e.g., an 
antihistamine and an anticholinergic. The agency is not changing the 
classification of any of these combinations because they do not contain 
an antitussive component. Thus, these combinations are not pertinent to 
combinations that include an antitussive that is also an antihistamine.

B. OTC cough-cold combinations containing: (1) An oral antitussive and 
an antihistamine if the antitussive is also a antihistamine or (2) an 
antihistamine and an oral antitussive if the antihistamine is also an 
antitussive.

    The Panel recommended a Category II classification for combinations 
containing: (1) An oral antitussive and an antihistamine if the 
antitussive is also a Category I antihistamine, and (2) an 
antihistamine and an oral antitussive if the antihistamine is also a 
Category I antitussive (41 FR 38312 at 38326). Such combinations 
include diphenhydramine and dextromethorphan or diphenhydramine and 
chlorpheniramine. The Panel stated that the combinations are not safe 
because the side effects of two drugs having the same action may 
combine. For example, the drowsiness effect of each ingredient may be 
additive and result in an unacceptable level of 
[[Page 10289]] drowsiness for the combination drug product.
    In the proposed rule for OTC cough-cold combination drug products 
(53 FR 30522 at 30539), FDA did not include any specific OTC cough-cold 
combination drug products containing diphenhydramine citrate or 
diphenhydramine hydrochloride as oral antitussive active ingredients. 
These ingredients were not included in the final monograph for OTC 
antitussive drug products because of a lack of publicly available data 
that would support the antitussive effectiveness of diphenhydramine. 
(See the Federal Register of October 19, 1983, 48 FR 48576.) However, 
the agency did discuss combinations containing a drug that is both an 
antitussive and an antihistamine (such as diphenhydramine) combined 
with another oral antitussive or antihistamine (53 FR 30522 at 30539). 
The agency considered such products to be combinations containing two 
ingredients from the same pharmacologic group and proposed a Category 
III classification based on the agency's ``General Guidelines for OTC 
Drug Combination Products'' (Ref. 1). Under the guidelines, Category I 
active ingredients from the same therapeutic category that have the 
same mechanism of action should not ordinarily be combined unless there 
is some advantage over the single ingredient in terms of enhanced 
effectiveness, safety, patient acceptance, or quality of formulation. 
However, the guidelines also state that such ingredients may be 
combined in selected circumstances to treat the same symptoms or 
conditions if the combination meets the OTC drug combination policy in 
all respects, the combination offers some advantage over the active 
ingredients used alone, and the combination is, on a benefit-risk 
basis, equal to or better than each of the active ingredients used 
alone at its therapeutic dose.
    Accordingly, the agency is proposing to place combinations 
containing a drug recognized as both an antitussive and an 
antihistamine with another oral antitussive and antihistamine in 
Category III. At the present time, this proposal only involves 
combinations containing diphenhydramine citrate or diphenhydramine 
hydrochloride with any monograph antihistamine in Sec. 341.12 or any 
monograph antitussive in Sec. 341.14. The agency is revising proposed 
Sec. 341.40(d), (e), and (f) to replace the phrase ``Any single 
antihistamine active ingredient identified in Sec. 341.12 * * *'' with 
the phrase ``Any single antihistamine active ingredient identified in 
Sec. 341.12(a) through (e) and (h) through (m) * * *.'' This revision 
specifically excludes combinations containing diphenhydramine citrate 
or diphenhydramine hydrochloride as an antihistamine with an 
antitussive.
    The agency is also revising proposed Sec. 341.40(d), (e), and (f) 
to replace the phrase ``any single oral antitussive active ingredient 
identified in Sec. 341.14(a) * * *'' with the phrase ``any single oral 
antitussive active ingredient identified in Sec. 341.14(a)(1) through 
(a)(4) * * *.'' This revision specifically excludes combinations 
containing diphenhydramine citrate or diphenhydramine hydrochloride as 
an antitussive with an antihistamine.
    The agency has also considered combinations containing a dose of 
diphenhydramine as the oral antitussive component and an additional 
dose of diphenhydramine as the antihistamine. The agency concludes that 
such a combination would contain too large a dose of diphenhydramine to 
be safe. Thus, the agency is proposing that such a combination be 
Category II.
    The use of a single dose of diphenhydramine as an antitussive and 
antihistamine for treating concurrent symptoms in either a single-
ingredient or combination drug product is discussed in section III.

Reference

    (1) Food and Drug Administration ``General Guidelines for OTC 
Drug Combination Products, September 1976,'' Docket No. 78D-0322, 
Dockets Management Branch.

III. Use of a Single Dose of Diphenhydramine Citrate or 
Diphenhydramine Hydrochloride as an Antitussive and Antihistamine 
for Treating Concurrent Symptoms (in Either a Single-Ingredient or 
Combination Drug Product)

    In the Federal Register of December 9, 1992 (57 FR 58378), the 
agency proposed to amend the final monograph for OTC antitussive drug 
products to add diphenhydramine citrate and diphenhydramine 
hydrochloride. In response, one comment stated that a single-ingredient 
drug product containing diphenhydramine hydrochloride for concurrent 
use as both an antihistamine and an antitussive should be labeled with 
a broader dosing range (e.g., diphenhydramine hydrochloride, 25 to 50 
milligrams (mg) every 4 to 6 hours, not to exceed 300 mg in 24 hours) 
to eliminate confusion to consumers (Ref. 1). The comment also 
contended that the broader dosage range should be permitted to provide 
the maximum antihistamine effectiveness for consumers. In addition, the 
comment stated that the labeling of products for concurrent 
antihistamine/antitussive use should include the appropriate warnings 
for both indications.
    The Panel believed that the interests of consumers are best served 
by exposing the user of OTC drug products to the smallest number of 
ingredients possible at the lowest possible dosage consistent with a 
satisfactory level of effectiveness (41 FR 38312 at 38322). Thus, an 
OTC drug product in which diphenhydramine citrate or diphenhydramine 
hydrochloride serves both as the antitussive and antihistamine 
component for treating concurrent symptoms would reduce the number of 
ingredients in the product. For example, a Category I combination drug 
product containing diphenhydramine as an antihistamine and antitussive 
combined with a nasal decongestant would contain only two ingredients. 
Such a combination would contain one less ingredient than a similar 
combination product containing three different ingredients for the same 
therapeutic uses. Similarly, an antihistamine-antitussive combination 
could contain only diphenhydramine to serve both functions.
    In a final rule that amended the OTC antitussive monograph to 
include diphenhydramine citrate and diphenhydramine hydrochloride (59 
FR 29172), the agency determined that the available clinical data and 
marketing history of products containing these ingredients for 
antitussive use do not support a broader dosage range. The agency 
concluded that it could not generally recognize as safe and effective 
an antitussive dosage (25 to 50 mg every 4 to 6 hours for 
diphenhydramine hydrochloride) that is not supported by clinical data. 
The dosage for diphenhydramine hydrochloride in Sec. 341.74(d)(1)(v) of 
the antitussive monograph (21 CFR 341.74(d)(1)(v)) reads:

    Adults and children 12 years of age and over: oral dosage is 25 
milligrams every 4 hours, not to exceed 150 milligrams in 24 hours, 
or as directed by a doctor. Children 6 to under 12 years of age: 
oral dosage is 12.5 milligrams every 4 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.

The dosage for diphenhydramine citrate in Sec. 341.74(d)(1)(iv) of the 
antitussive monograph (21 CFR 341.74(d)(1)(iv)) reads:

    Adults and children 12 years of age and over: oral dosage is 38 
milligrams every 4 hours, not to exceed 228 milligrams in 24 hours, 
or as directed by a doctor. Children 6 [[Page 10290]] to under 12 
years of age: oral dosage is 19 milligrams every 4 hours, not to 
exceed 114 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.

The dosage for diphenhydramine hydrochloride in Sec. 341.72(d)(7) of 
the antihistamine monograph (21 CFR 341.72(d)(7)) reads:

    Adults and children 12 years of age and over: oral dosage is 25 
to 50 milligrams every 4 to 6 hours, not to exceed 300 milligrams in 
24 hours, or as directed by a doctor. Children 6 to under 12 years 
of age: oral dosage is 12.5 to 25 milligrams every 4 to 6 hours, not 
to exceed 150 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.

The dosage for diphenhydramine citrate in Sec. 341.72(d)(6) of the 
antihistamine monograph (21 CFR 341.72(d)(6)) reads:

    Adults and children 12 years of age and over: oral dosage is 38 
to 76 milligrams every 4 to 6 hours, not to exceed 456 milligrams in 
24 hours, or as directed by a doctor. Children 6 to under 12 years 
of age: oral dosage is 19 to 38 milligrams every 4 to 6 hours, not 
to exceed 228 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.

    The agency believes that an OTC drug product containing 
diphenhydramine citrate or diphenhydramine hydrochloride that is 
labeled both as an antitussive and an antihistamine should conform to 
the same labeling restrictions that apply to combination drug products 
containing a different antitussive and antihistamine ingredient. In the 
tentative final monograph for OTC cough-cold combination drug products, 
the agency proposed that when there is a difference in the directions 
established for the individual ingredients in a combination drug 
product, e.g., when the time intervals or age limitations for 
administration of the individual ingredients differ, the directions for 
the combination product may not exceed any maximum dosage limits 
established for the individual ingredients in the applicable OTC drug 
monograph (53 FR 30522 at 30554). Therefore, when diphenhydramine 
citrate or diphenhydramine hydrochloride is labeled for both 
antitussive and antihistamine use, the limiting factor for directions 
for use for both the dosage amount and dosing interval for OTC labeling 
is the antitussive dosage in Sec. 341.74(d)(1)(iv) and (d)(1)(v). 
However, the limiting factor for directions for use for professional 
labeling is the antihistamine dosage in Sec. 341.90(j) and (k) (21 CFR 
341.90(j) and (k)), respectively. As noted above, the Panel believed 
that the interests of consumers are best served by exposing the user of 
OTC drug products to the smallest number of ingredients possible at the 
lowest possible dosage consistent with a satisfactory level of 
effectiveness (41 FR 38312 at 38322).
    The comment also questioned how the statements of identity, 
indications, and warnings required for both OTC antitussive and 
antihistamine drug products could be combined when the product contains 
diphenhydramine for concurrent antitussive and antihistamine use. The 
agency has determined that the labeling of such products should conform 
to the labeling requirements for combination drug products containing 
an antitussive and an antihistamine. The proposed labeling section for 
OTC cough-cold combinations (Sec. 341.85) states that the statements of 
identity, indications, and warnings may be combined to eliminate 
duplicative wording or phrases so that the resulting information is 
clear and understandable (53 FR 30522 at 30562).
    When applied to diphenhydramine for concurrent use, the statement 
of identity would be ``antihistamine/cough suppressant'' or 
``antihistamine/antitussive (cough suppressant).'' The indications 
would be combined from Secs. 341.72(b) and 341.74(b). The warnings 
would be combined from Sec. 341.72(c)(1), (c)(2), (c)(4), and (c)(6) 
and Sec. 341.74(c)(1), (c)(2), (c)(3), and (c)(4). The warnings for 
diphenhydramine for antitussive use in Sec. 341.74(c)(4) encompass all 
of the same warnings for diphenhydramine for antihistamine use in 
Sec. 341.72(c)(1), (c)(2), (c)(4), and (c)(6). In addition, the product 
would need to have the required warnings for antitussive use in 
Sec. 341.74(c)(1), (c)(2), and (c)(3), as applicable (depending on the 
ages for which the product is labeled). Thus, an easy rule to follow 
when using diphenhydramine citrate or diphenhydramine hydrochloride as 
a single ingredient for both antihistamine and antitussive use is to 
follow all of the warnings in Sec. 341.74(c) of the antitussive 
monograph. This example illustrates how a single uniform warning 
results when the duplicative words or phrases from the respective 
warnings are eliminated.
    Accordingly, the agency is proposing the following labeling for 
drug products that contain diphenhydramine citrate or diphenhydramine 
hydrochloride for concurrent antitussive and antihistamine use: 
Labeling of drug products containing diphenhydramine citrate or 
diphenhydramine hydrochloride for concurrent antitussive and 
antihistamine use either as a single ingredient product or as a single 
ingredient in combination with other active ingredients. The statements 
of identity, indications, and warnings required for antitussive and 
antihistamine use may be combined to eliminate duplicative words or 
phrases so that the resulting information is clear and understandable. 
The directions for OTC labeling shall follow Sec. 341.74(d)(1)(iv) or 
(d)(1)(v), as applicable. The directions for professional labeling 
shall follow Sec. 341.90(j) or (k), as applicable.
    The agency notes that allowing the use of diphenhydramine in the 
same product as both an antitussive and antihistamine for treating 
concurrent symptoms is a new concept. Therefore, the agency would like 
to receive public comment on the proposed new concept and on the 
proposed labeling approach before marketing begins. Although the agency 
is proposing in this amendment to the cough-cold combination tentative 
final monograph to allow the use of diphenhydramine in the same product 
as both an antitussive and an antihistamine, OTC marketing may not 
begin at this time. The agency is providing a short comment period of 
75 days and plans to issue a notice of enforcement policy at a later 
date to state whether marketing may begin prior to the issuance of the 
final monograph for OTC cough-cold combination drug products.

Reference

    (1) Comment No. C0001, Docket No. 89P-0040, Dockets Management 
Branch.

IV. Summary of the Agency's Proposals for OTC Cough-Cold 
Combinations Containing Diphenhydramine as an Antitussive

    The agency has reviewed all combinations containing an oral 
antitussive and/or an antihistamine that were classified as Category I, 
II, or III in the tentative final monograph for OTC cough-cold 
combination drug products (53 FR 30522 at 30556 and 30557), to clarify 
the use of diphenhydramine citrate and diphenhydramine hydrochloride as 
antitussive active ingredients in these combinations. For the 
convenience of the reader, the following table is included as a summary 
of the proposed classification changes by the agency of combinations 
containing an antitussive in the tentative final monograph for OTC 
cough-cold combination drug products (53 FR 30522 at 30556 and 30557) 
and the proposed classification by the agency of these combinations 
when the antitussive or the antihistamine active ingredient is either 
diphenhydramine citrate or diphenhydramine hydrochloride. Table 3 
includes only [[Page 10291]] the proposed changes in classification 
made in Sec. 341.40 of the cough-cold combination drug products 
tentative final monograph. All other combination classifications remain 
the same:

--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                         Table 3                                                                        
---------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                Tentative Final Monograph Proposed                New Proposed Classification for       
                 Cold-Cough Combinations                                  Classification                      Dephenhydramine-Containing Combinations   
--------------------------------------------------------------------------------------------------------------------------------------------------------
Oral antitussive and expectorant (if labeled for                                                                                                        
 nonproductive cough)                                                                                 I                                              II 
Oral antitussive and expectorant and oral nasal                                                                                                         
 decongestant (if labeled for nonproductive cough)                                                    I                                              II 
Oral antitussive and bronchdilator used as an                                                                                                           
 antitussive (if labeled for productive cough)                                                      III                                              II 
Oral antitussive and expectorant (if labeled for                                                                                                        
 productive cough)                                                                                  III                                              II 
Oral antitussive and expectorant and oral nasal                                                                                                         
 decongestant (if labeled for productive cough)                                                     III                                              II 
Analgesic-antipyretic(s) and oral antitussive and                                                                                                       
 expectorant and oral nasal decongestant                                                            III                                              II 
Antihistamine and oral antitussive (if labeled ``May                                                                                                    
 cause marked drowsiness'')                                                                           I                                             III 
Analgesic-antipyretic(s) and oral antitussive and oral                                                                                                  
 nasal decongestant and antihistamine                                                                 I                                             III 
Antihistamine and oral antitussive and oral nasal                                                                                                       
 decongestant                                                                                         I                                             III 
--------------------------------------------------------------------------------------------------------------------------------------------------------

    1. The agency is revising proposed Sec. 341.40(d), (e), and (f) to 
replace the phrase ``Any single antihistamine active ingredient 
identified in Sec. 341.12 * * *'' with the phrase ``any single 
antihistamine active ingredient identified in Sec. 341.12(a) through 
(e) and (h) through (m) * * *'' to exclude the ingredients 
diphenhydramine citrate and diphenhydramine hydrochloride. (See section 
II.B.)
    2. The agency is revising Sec. 341.40(d) through (g) and (i) to 
replace the phrase ``Any single oral antitussive active ingredient 
identified in Sec. 341.14(a) * * *'' with the phrase ``Any single oral 
antitussive active ingredient identified in Sec. 341.14(a)(1) through 
(a)(4) * * *'' to exclude the ingredients diphenhydramine citrate and 
diphenhydramine hydrochloride. (See sections II.A.(i) and II.B.)
    3. The agency is proposing to include diphenhydramine citrate and 
diphenhydramine hydrochloride in combinations specified in 
Sec. 341.40(h), (j), (k), (q), (u), (w), (x), and (z). (See section 
II.A.(ii).)
    4. The agency is proposing in Sec. 341.40(d), (e), and (f) the use 
of diphenhydramine citrate in Secs. 341.12(f) and 341.14(a)(5) or 
diphenhydramine hydrochloride in Secs. 341.12(g) and 341.14(a)(6) as 
both the antihistamine and the antitussive active ingredient provided 
that the product is labeled according to Sec. 341.70.
    5. The agency is revising Sec. 341.40(f) and (k) to include the 
specific section numbers for allowed internal analgesic ingredients.
    6. In the oral health care tentative final monograph published on 
September 24, 1991 (56 FR 48302), the agency redesignated the active 
anesthetic/analgesic ingredients previously proposed in Sec. 356.10 as 
Sec. 356.12. Accordingly, the agency is revising Sec. 341.40(j), (q), 
(x), and (z) to replace the phrase ``any single oral anesthetic/
analgesic active ingredient identified in Sec. 356.10 * * *'' with the 
phrase ``any single oral anesthetic/analgesic active ingredient 
identified in Sec. 356.12 * * *''.
    7. The agency is proposing to add to Sec. 341.70 labeling for 
diphenhydramine-containing drug products for concurrent antitussive and 
antihistamine use under the heading: Labeling of drug products 
containing diphenhydramine citrate or diphenhydramine hydrochloride for 
concurrent antitussive and antihistamine use either as a single 
ingredient product or as a single ingredient in combination with other 
active ingredients. (See section III.)

V. Effective Date

    The agency advises that any final rule resulting from this proposed 
rule will be effective 12 months after its date of publication in the 
Federal Register. On or after that date, any OTC drug product that is 
not in compliance may not be initially introduced or initially 
delivered for introduction into interstate commerce unless it is the 
subject of an approved application. Further, any OTC drug product 
subject to the rule that is repackaged or relabeled after the effective 
date of the rule must be in compliance with the rule regardless of the 
date that the product was initially introduced or initially delivered 
for introduction into interstate commerce. Manufacturers are encouraged 
to comply voluntarily with the rule at the earliest possible date.

VI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the 
[[Page 10292]] proposed rule is not a significant regulatory action as 
defined by the Executive Order and so is not subject to review under 
the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. This proposed rule clarifies the use of 
diphenhydramine citrate or diphenhydramine hydrochloride as an 
antitussive active ingredient in OTC cough-cold combination drug 
products and proposes marketing of either a single-ingredient or a 
combination drug product containing one of these ingredients for 
concurrent antitussive and antihistamine use. Manufacturers may market 
such products at their option when marketing is allowed to begin. (See 
marketing discussion in section III.) Accordingly, the agency certifies 
that the proposed rule will not have a significant economic impact on a 
substantial number of small entities. Therefore, under the Regulatory 
Flexibility Act, no further analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on OTC 
cough-cold combination drug products. Comments regarding the impact of 
this rulemaking on these drug products should be accompanied by 
appropriate documentation.
    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

VII. Request for Comments

    Interested persons may, on or before May 9, 1995, submit to the 
Dockets Management Branch (address above) written comments or 
objections. Three copies of all comments or objections are to be 
submitted, except that individuals may submit one copy. Comments and 
objections are to be identified with the docket number found in 
brackets in the heading of this document and may be accompanied by a 
supporting memorandum or brief. Comments and objections may be seen in 
the office above between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 341

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 341 (as proposed in the Federal Register of 
August 12, 1988 (53 FR 30522)) be amended as follows:

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

    1. The authority citation for 21 CFR part 341 continues to read as 
follows:
    Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371).

    2. Section 341.40 is amended by revising paragraphs (d) through 
(k), (q), (u), (w), (x), and (z) to read as follows:


Sec. 341.40  Permitted combinations of active ingredients.

* * * * *
    (d) Any single antihistamine active ingredient identified in 
Sec. 341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) provided that the product is labeled 
according to Sec. 341.85(c)(5). Diphenhydramine citrate in 
Secs. 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in 
Secs. 341.12(g) and 341.14(a)(6) may be both the antihistamine and the 
antitussive active ingredient provided that the product is labeled 
according to Sec. 341.70.
    (e) Any single antihistamine active ingredient identified in 
Sec. 341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec. 341.20(a). Diphenhydramine citrate 
in Secs. 341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in 
Secs. 341.12(g) and 341.14(a)(6) may be both the antihistamine and the 
antitussive active ingredient provided that the product is labeled 
according to Sec. 341.70.
    (f) Any single antihistamine active ingredient identified in 
Sec. 341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec. 341.20(a) and any single 
analgesic-antipyretic active ingredients identified in Sec. 343.10 of 
this chapter, or any combination of acetaminophen with other analgesic-
antipyretic active ingredients identified in Sec. 343.20(a) of this 
chapter, or any aspirin and antacid combination identified in 
Sec. 343.20(b)(3). Diphenhydramine citrate in Secs. 341.12(f) and 
341.14(a)(5) or diphenhydramine hydrochloride in Secs. 341.12(g) and 
341.14(a)(6) may be both the antihistamine and the antitussive active 
ingredient provided that the product is labeled according to 
Sec. 341.70.
    (g) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) may be combined with any single 
expectorant active ingredient identified in Sec. 341.18.
    (h) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec. 341.20(a) 
provided the product contains only the labeling claims identified in 
this paragraph.
    (i) Any single oral antitussive drug ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec. 341.20(a) and 
any single expectorant active ingredient identified in Sec. 341.18.
    (j) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral 
anesthetic/analgesic active ingredient identified in Sec. 356.12 of 
this chapter provided that the product is available in a solid dosage 
form to be dissolved in the mouth and swallowed and provided the 
product contains only the labeling claims identified in this paragraph.
    (k) Any single oral antitussive drug ingredient identified in 
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec. 341.20(a) and 
any single analgesic-antipyretic active ingredients identified in 
Sec. 343.10 of this chapter, or any combination of acetaminophen with 
other analgesic-antipyretic active ingredients identified in 
Sec. 343.20(a) of this chapter, or any aspirin and antacid combination 
identified in Sec. 343.20(b)(3) provided the product contains only the 
labeling claims identified in this paragraph and provided the product 
contains only the labeling claims identified in this paragraph.
* * * * *
    (q) Any single oral nasal decongestant active ingredient identified 
in Sec. 341.20(a) may be combined with any single oral antitussive 
active ingredient identified in Sec. 341.14(a)(1) through (a)(6) and 
any single oral anesthetic/analgesic active ingredient identified in 
Sec. 356.12 of this chapter provided that the product is available in a 
solid dosage form to be dissolved in the mouth and swallowed and 
provided the [[Page 10293]] product contains only the labeling claims 
identified in this paragraph.
* * * * *
    (u) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral 
demulcent active ingredient identified in Sec. 356.18 of this chapter 
provided that the product is available in a solid dosage form to be 
dissolved in the mouth and swallowed and provided the product contains 
only the labeling claims identified in this paragraph.
* * * * *
    (w) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec. 341.20(a) and 
any single oral demulcent active ingredient identified in Sec. 356.18 
of this chapter provided that the product is available in a solid 
dosage form to be dissolved in the mouth and swallowed and provided the 
product contains only the labeling claims identified in this paragraph.
    (x) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral 
anesthetic/analgesic active ingredient identified in Sec. 356.12 of 
this chapter and any single oral demulcent active ingredient identified 
in Sec. 356.18 of this chapter provided that the product is available 
in a solid dosage form to be dissolved in the mouth and swallowed and 
provided the product contains only the labeling claims identified in 
this paragraph.
* * * * *
    (z) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(6) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec. 341.20(a) and 
any single oral anesthetic/analgesic active ingredient identified in 
Sec. 356.12 of this chapter and any single oral demulcent active 
ingredient identified in Sec. 356.18 of this chapter provided that the 
product is available in a solid dosage form to be dissolved in the 
mouth and swallowed and provided the product contains only the labeling 
claims identified in this paragraph.
    3. New Sec. 341.70 is added to subpart C to read as follows:


Sec. 341.70  Labeling of drug products containing diphenhydramine 
citrate or diphenhydramine hydrochloride for concurrent antitussive and 
antihistamine use either as a single ingredient product or as a single 
ingredient in combination with other active ingredients.

    The statements of identity, indications, and warnings required for 
antitussive and antihistamine use may be combined to eliminate 
duplicative words or phrases so that the resulting information is clear 
and understandable. The directions for OTC labeling shall follow 
Sec. 341.74(d)(1)(iv) or (d)(1)(v), as applicable. The directions for 
professional labeling shall follow Sec. 341.90(j) or (k), as 
applicable.

    Dated: January 31, 1995.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 95-4464 Filed 2-22-95; 8:45 am]
BILLING CODE 4160-01-F