[Federal Register: January 5, 2005 (Volume 70, Number 3)]
[Proposed Rules]               
[Page 741-746]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05ja05-33]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 357

[Docket No. 1982N-0166]
RIN 0910-AF51

 
Orally Administered Drug Products for Relief of Symptoms 
Associated With Overindulgence in Food and Drink for Over-the-Counter 
Human Use; Proposed Amendment of the Tentative Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the tentative final monograph (TFM) for over-the-counter (OTC) orally 
administered drug products for relief of symptoms associated with 
overindulgence in food and drink to include an additional use for 
products that contain bismuth subsalicylate as an active ingredient 
labeled for the relief of symptoms of upset stomach due to 
overindulgence resulting from food and drink. This proposal is part of 
FDA's ongoing review of OTC drug products.

DATES: Submit written or electronic comments by April 5, 2005. Please 
see section X of this document for the proposed effective date of any 
final rule that may publish based on this proposal.

ADDRESSES: You may submit comments, identified by Docket No. 1982N-0166 
or RIN 0910-AF51, by any of the following methods:
     Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting comments on the agency Web site.
     E-mail: fdadockets@oc.fda.gov. Include Docket No. 1982N-
0166 or RIN 0910-AF51 in the subject line of your e-mail message.
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management, 5630 Fishers Lane, rm. 
1061, Rockville, MD 20852.
Instructions: All submissions received must include the agency name and 
Docket No. or Regulatory Information Number (RIN) for this rulemaking. 
All comments received will be posted without change to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments
, including any personal information 

provided. For detailed instructions on submitting comments and 
additional information on the rulemaking process, see the ``Request for 
Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
Docket: For access to the docket to read background documents or 
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecommentsand/or the 

Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2307.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of October 1, 1982 (47 FR 43540), FDA 
published an advance notice of proposed rulemaking to establish a 
monograph for OTC orally administered drug products for relief of 
symptoms associated with overindulgence in alcohol and food, together 
with the recommendations of the Advisory Review Panel on OTC 
Miscellaneous Internal Drug Products (the Panel), which was the 
advisory review panel responsible for evaluating data on the active 
ingredients in these drug products (Sec.  330.10(a)(6) (21 CFR 
330.10(a)(6))).
    In the Federal Register of December 24, 1991 (56 FR 66742), FDA 
published the proposed rule (in the form of a TFM) for OTC orally 
administered drug products for relief of symptoms associated with 
overindulgence in food and drink. In the Federal Register of May 5, 
1993 (58 FR 26886), FDA proposed to amend the overindulgence TFM to 
include a Reye's syndrome warning for OTC drug products containing 
bismuth subsalicylate. In the

[[Page 742]]

Federal Register of April 17, 2003 (68 FR 18861), FDA published a final 
rule to revise the Reye's syndrome warning (Sec.  201.314(h) (21 CFR 
201.314(h))) to include OTC drug products containing nonaspirin 
salicylates (e.g., bismuth subsalicylate) as active ingredients. FDA 
stated that there was no need to address this warning in a separate 
rule for overindulgence drug products containing bismuth subsalicylate 
(68 FR 18861 at 18862). Thus, the April 17, 2003, final rule completed 
the May 5, 1993, proposed rule. Products containing bismuth 
subsalicylate as an active ingredient must contain the required Reye's 
syndrome warning statement as of April 19, 2004, except that products 
with annual sales less than $25,000 have until April 18, 2005, to be in 
compliance.
    In the Federal Register of March 17, 1999 (64 FR 13254), FDA 
established a standardized format and content for the labeling of all 
OTC drug products (see Sec.  201.66). The labeling in the TFM and the 
labeling in this amendment are not in that format. However, the 
labeling in the final monograph (FM) will incorporate the standardized 
labeling format and content. In response to the TFM, FDA received a 
number of comments and is addressing part of one comment in this 
document. The remaining comments will be addressed in the final rule. 
All ``OTC Volumes'' cited throughout this document refer to information 
on public display in the Division of Dockets Management (see 
ADDRESSES).

II. The Comment's Recommendation, Arguments, and Data

    One comment recommended that FDA include combination upset stomach/
antiflatulent (antigas) drug products containing bismuth subsalicylate 
and simethicone in the overindulgence monograph for the relief of upset 
stomach and gas due to overindulgence in food and drink. The comment 
provided the following arguments and data to support its 
recommendation.
     FDA's ``General Guidelines for OTC Drug Combination 
Products, September 1978'' (Ref. 1) provide that Category I active 
ingredients from different therapeutic categories may be combined to 
treat different symptoms concurrently if each ingredient is present 
within its established safe and effective dosage range, and the 
combination meets the OTC drug combination policy in all other 
respects. FDA's OTC drug combination regulations (Sec.  
330.10(a)(4)(iv)) provide that an OTC drug may combine two or more safe 
and effective active ingredients and may be generally recognized as 
safe and effective when each active ingredient makes a contribution to 
the claimed effect(s); when combining of the active ingredients does 
not decrease the safety or effectiveness of any of the individual 
active ingredients; and when the combination, when used under adequate 
directions for use and warnings against unsafe use, provides rational 
concurrent therapy for a significant proportion of the target 
population. A combination drug product containing bismuth subsalicylate 
and simethicone would combine two Category I active ingredients as 
specified in these Guidelines and meet the requirements of this 
regulation.
     FDA proposed bismuth subsalicylate as safe and effective 
for the relief of symptoms of upset stomach associated with 
overindulgence in food and drink in the TFM, and simethicone is 
included in the antiflatulent monograph (21 CFR part 332). Bismuth 
subsalicylate acts in the stomach to relieve upset stomach/indigestion 
symptoms such as nausea, heartburn, and fullness, while simethicone 
acts in the stomach to break up gas bubbles resulting from 
overindulgence in food and drink. Together, these active ingredients 
will provide relief from upset stomach symptoms occurring in the 
presence of gas.
     Combining the active ingredients does not decrease the 
safety and effectiveness of either ingredient. The comment cited data 
to support that (1) Bismuth subsalicylate does not decrease the foam-
reducing capacity of simethicone (Ref. 2), (2) serum salicylate 
bioavailability of a combination of bismuth subsalicylate-simethicone 
was equivalent to bismuth subsalicylate alone in dogs (Ref. 3), and (3) 
the combination and bismuth subsalicylate alone in rats provided 
equivalent stomach protection against alcohol (Ref. 4).
     The combination provides rational concurrent therapy for a 
significant proportion of the target population. The comment noted a 
consumer study of 285 subjects suffering from upset stomach due to 
overindulgence in which 56 percent of the subjects reported gas as one 
of their symptoms (Ref. 5). The comment mentioned another consumer 
study of 159 adults who reported having gas concurrently with symptoms 
for which bismuth subsalicylate has been shown to be effective (Ref. 
6). The percent of adults reporting gas with each symptom included: 
Fullness/bloating (57), upset stomach (55), indigestion (44), and 
heartburn (24).
     Antacid-simethicone combination products were included in 
the antacid monograph (21 CFR part 331) and the antiflatulent monograph 
without any supporting clinical data. FDA's determination to allow this 
combination was based on a reasonable expectation that simethicone will 
be effective if used in combination with an antacid drug product (38 FR 
31260 at 31266, November 12, 1973). Further, FDA has proposed that any 
antacid covered by the antacid monograph may be labeled ``for the 
relief of * * * upset stomach associated with * * * overindulgence in 
food and drink'' (56 FR 66754 at 66756, December 24, 1991). FDA did not 
review any clinical data to support the indication of upset stomach and 
gas due to overindulgence in food and drink.

III. FDA's Evaluation of the Comment's Recommendation

    FDA has evaluated the comment's recommendation and reconsidered the 
Panel's review of bismuth subsalicylate for the relief of symptoms of 
upset stomach associated with overindulgence in food and drink. The 
Panel stated that upset stomach that occurs as a result of 
overindulgence in food and drink consists of a group of symptoms that 
includes heartburn, fullness, and nausea (47 FR 43540 at 43543 and 
43545). One of the indications statements that the Panel recommended 
for products containing bismuth subsalicylate included these symptoms: 
``For the relief of upset stomach associated with'' (select one or more 
of the following: ``nausea,'' ``heartburn,'' and ``fullness'') ``due to 
overindulgence in the combination of food and drink.'' (See 47 FR 43540 
at 43550 and 43558.) FDA proposed this indication statement without the 
words ``the combination of'' in Sec.  357.950(b)(2) of the TFM (see 56 
FR 66742 at 66751).
    The Panel discussed the consumer study of 285 subjects (Ref. 5) (47 
FR 43540 at 43545), cited by the comment, and noted that 96 percent of 
the subjects had at least one of the symptoms of ``gas (fullness), 
heartburn (or acid indigestion), or nausea'' and that 56 percent [the 
highest percentage] reported gas as one of their symptoms. The Panel 
cited studies by Newsom (Ref. 7) and by Berkowitz (Ref. 8) (47 FR 43540 
at 43548 to 43549) to support the effectiveness of bismuth 
subsalicylate for treating upset stomach due to overindulgence. The 
Newsom study was subsequently published in the Archives of Internal 
Medicine (Ref. 9).
    Newsom conducted a randomized, placebo-controlled, double-blind, 
multiple-crossover study (Refs. 7 and 9) to evaluate the effectiveness 
of bismuth

[[Page 743]]

subsalicylate to relieve symptoms in subjects with a history of 
episodic, acute (having a short and relatively severe course) 
indigestion. The study involved 48 adult subjects 18 to 49 years old 
(20 men, 28 women). Two additional subjects began the study but were 
later excluded by the investigator because of abnormal laboratory 
values. The study medication consisted of either 16.7 milligrams per 
milliliter (mg/mL) of bismuth subsalicylate suspended in the vehicle or 
a placebo of vehicle only. The two preparations were similar in 
appearance, flavor, and viscosity. Each subject received three bottles 
of each formulation with a computer-generated random sequence of use 
for treating six episodes over a 7-month period. The subjects were 
instructed to take the study medication only when they experienced two 
or more of the symptoms and to take 30 mL every 30 minutes as needed 
for a total of eight doses (up to 240 minutes). Subjects recorded 
specific symptoms and the time they first occurred, rating symptom 
severity on a 10-point scale 15 and 30 minutes after each dose. 
Subjects reported the time when relief occurred. After six episodes, 
each subject evaluated each preparation three times.
    Newsom defined indigestion or acute gastrointestinal discomfort as 
a symptom complex consisting of two or more of the following symptoms 
occurring during or after ingestion of food: Nausea, heartburn, upper-
abdominal pain, flatulence (gas) and eructation (belching), sense of 
fullness, or a feeling of abdominal distention. Stedman's Medical 
Dictionary (Ref. 10) defines indigestion as a nonspecific term for a 
variety of symptoms resulting from a failure of proper digestion and 
absorption of food in the alimentary tract [relating to the organs of 
digestion]. FDA notes that the investigator's definition of indigestion 
or acute gastrointestinal discomfort is consistent with the Stedman's 
definition in that the dictionary's term is nonspecific and the 
investigator's symptoms relate to the digestive system.
    The 48 test subjects had no significant differences in reported 
symptoms or identified causes in the six individual episodes of 
symptoms. Eating specific foods was the most commonly identified cause 
of symptoms, followed by overeating. The overall relief of symptoms 
showed more episodes treated with bismuth subsalicylate were relieved 
(132/144) than were episodes treated with placebo (121/144). However, 
the difference between the two groups was not statistically significant 
(0.05< p< 0.10). However, when time to relief was evaluated in 30-minute 
intervals, the episodes treated with bismuth subsalicylate were 
relieved in 90 minutes (median) compared to 120 minutes (median) for 
episodes treated with placebo. The difference was statistically 
significant (p< 0.01). In addition, the differences in time to relief 
were significant at the time intervals of 31 to 60, 61 to 90, and 91 to 
120 minutes (p< 0.01). Beginning at 30 to 45 minutes post-medication, a 
statistically significant more rapid decrease in severity of nausea, 
heartburn, flatulence and eructation, and sense of fullness occurred in 
the subjects receiving bismuth subsalicylate compared to subjects 
receiving placebo. The feeling of abdominal distension was less severe 
at 90 minutes with bismuth subsalicylate, but the severity of upper 
abdominal pain was no different with either treatment. Comparing the 
time to relief shows that bismuth subsalicylate provided significantly 
faster relief than placebo for nausea, heartburn, flatulence and 
eructation, and sense of fullness. FDA concludes that this study 
supports that bismuth subsalicylate relieves the symptoms of flatulence 
and eructation, which are symptoms from gas. The study also supports 
that bismuth subsalicylate relieves the sense of fullness, which might 
be related to gas.
    Berkowitz conducted a randomized, placebo-controlled, double-blind 
study (Ref. 8) to evaluate the effectiveness of bismuth subsalicylate 
to relieve gastrointestinal symptoms, commonly termed as ``upset 
stomach,'' from consumption of food and drink. One hundred thirty two 
healthy adult subjects fasted for 6 hours and then were provided 
unlimited quantities of provocative food and drink. The subjects were 
provided a diary to record eight symptoms, degree of discomfort (none, 
mild, moderate, severe), and the time of occurrence. The symptoms were:
     stomach queasiness/nausea
     heartburn
     sense of fullness/bloated feeling
     belching
     bitter or acid taste in mouth
     passing gas/wind
     stomach pain/cramps
     other symptoms
The subjects were instructed to take 30 mL of the test medication when 
symptoms first occurred and to repeat the dose every 30 to 60 minutes, 
if needed, up to eight doses. The test medication (bismuth 
subsalicylate) and the placebo were prepared as white, opaque 
suspensions identical in flavor and viscosity. However, Berkowitz did 
not mention the concentration of the bismuth subsalicylate preparation. 
Subjects recorded the time the dose was taken and the degree of relief 
obtained (none, poor, good, excellent).
    Ninety-one of the 132 subjects developed symptoms that required 
medication, with 43 taking bismuth subsalicylate and 48 taking placebo. 
Comparison of the two groups showed no significant demographic or 
baseline differences. The number of subjects and the percent of 91 
total subjects reporting the symptoms were as follows:
     stomach queasiness/nausea - 50 (55%)
     heartburn - 48 (53%)
     sense of fullness/bloated feeling - 66 (73%)
     belching - 50 (55%)
     bitter or acid taste in mouth - 18 (20%)
     passing gas/wind - 30 (33%)
     stomach pain/cramps - 17 (19%)
The number of symptoms reported is greater than the number of subjects 
because subjects reported more than one symptom. Berkowitz performed a 
statistical analysis of the four relief categories for each symptom and 
for overall relief. Berkowitz found that bismuth subsalicylate was 
significantly more effective than placebo for each category except 
bitter/acid taste. When the analysis was done using (1) Two relief 
categories (none and poor counted as failure, and good and excellent 
counted as success) and (2) time to good or excellent relief for each 
symptom, Berkowitz found that bismuth subsalicylate was significantly 
more effective and provided significantly faster relief than placebo 
for relief of nausea, fullness, heartburn, belching, and overall 
relief. There was no statistical difference in relief of stomach pain/
cramps, passing gas, and bitter/acid taste. FDA finds that, although 
all data are not clearly shown in this study, the results support that 
bismuth subsalicylate is effective in relieving nausea, heartburn, 
fullness, and belching. FDA notes that the medical definitions of 
flatulence, eructation, and bloating are defined using the word gas. 
While ``fullness'' is not defined in Stedman's Medical Dictionary (Ref. 
10) or in Dorland's Illustrated Medical Dictionary (Ref. 11), Berkowitz 
combined the term ``fullness'' with the term ``bloating,'' which refers 
to abdominal distention from swallowing air or from intestinal gas, and 
showed that bismuth subsalicylate relieved fullness and bloating.
    FDA notes that, in evaluating the consumer study of 285 subjects 
(Ref. 5) (47 FR 43540 at 43545), the Panel noted that 96 percent of the 
subjects had at least one of the symptoms of gas (fullness), heartburn 
(or acid indigestion), or nausea, and that 56

[[Page 744]]

percent [the highest percentage] reported gas as one of their symptoms. 
Nonetheless, the Panel used the term ``fullness'' (and not ``gas'') in 
its proposed indication for overindulgence drug products containing 
bismuth subsalicylate (47 FR 43540 at 43558). FDA believes that the 
Panel also found that bismuth subsalicylate relieves gas due to 
overindulgence in food and drink, but chose to use the word 
``fullness'' instead in its recommended indications statement. FDA also 
points out that its current indications statement for OTC antiflatulent 
drug products containing simethicone in Sec.  332.30(b)(2) states: 
``(Select one of the following: `Alleviates' or `Relieves') (select one 
or more of the following: `bloating,' `pressure,' `fullness,' or 
`stuffed feeling') `commonly referred to as gas'.'' Thus, FDA already 
acknowledges that the term ``fullness'' encompasses the term ``gas.''
    As the comment noted, the combination of bismuth subsalicylate and 
simethicone is subject to FDA's combination drug policy (see section II 
of this document). However, FDA notes that a bismuth subsalicylate-
simethicone combination is different than the antacid-simethicone 
combination that the comment discussed. Simethicone is a monograph 
ingredient (see Sec.  332.10) for antiflatulent use (to relieve 
fullness and bloating commonly referred to as gas). Bismuth 
subsalicylate is not included in the antacid monograph but based on the 
information and analysis in this document has an antigas 
(antiflatulent) effect when relieving symptoms of overindulgence in 
food and drink. This analysis and finding are new information that the 
comment did not have when it proposed a bismuth subsalicylate-
simethicone combination product.
    FDA's regulation in Sec.  330.10(a)(4) sets forth the standard for 
determining whether a combination drug product may be generally 
recognized as safe and effective and not misbranded. Section 
330.10(a)(4)(iv) states that ``an OTC drug may combine two or more safe 
and effective active ingredients and may be generally recognized as 
safe and effective when each active ingredient makes a contribution to 
the claimed effect(s) * * *.'' FDA's ``General Guidelines for OTC Drug 
Combination Products, September 1978'' [``Combination Product 
Guidelines''] (Ref. 1) state that Category I active ingredients from 
the same therapeutic category [``antiflatulent'' in this case] that 
have the same mechanism of action may be combined in selected 
circumstances to treat the same symptoms if:
     The combination meets the OTC 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.
The ``Combination Product Guidelines'' (Ref. 1) list similar factors in 
assessing combination drug products with active ingredients from the 
same therapeutic category that have different mechanisms of action.
    FDA does not have any data on the antigas mechanism of action of 
bismuth subsalicylate to determine if it is the same or different from 
that of simethicone. FDA also has not received any data to date 
comparing the antigas effectiveness of a combination of the two 
ingredients versus either individual ingredient. Further, FDA is not 
aware of any combination product containing bismuth subsalicylate and 
simethicone having been marketed. Therefore, FDA needs data from 
clinical studies showing that the combination of bismuth subsalicylate 
and simethicone is equal to or better than [offers some advantage over] 
each of the individual active ingredients used alone at its therapeutic 
dose for this antigas use. FDA recommends that anyone interested in 
conducting such studies submit a protocol and meet with the agency 
before starting the studies. FDA will evaluate the other data (Refs. 2, 
3, and 4) that the comment provided to support this combination product 
when the clinical effectiveness studies are submitted to FDA.

IV. FDA's Proposed Amendment of the Tentative Final Monograph

    Based on the Newsom (Refs. 7 and 9) and Berkowitz (Ref. 8) studies, 
FDA has tentatively determined that bismuth subsalicylate is safe and 
effective for OTC use for the relief of upset stomach associated with 
belching and gas due to overindulgence in food and drink. FDA proposes 
to amend the definition of ``upset stomach due to overindulgence in 
food and drink'' proposed in Sec.  357.903 to add the symptoms 
``belching'' and ``gas'' and to amend the indications statement for 
bismuth subsalicylate proposed in Sec.  357.950(b)(2) to add 
``belching'' and ``gas'' as two additional symptoms that manufacturers 
may select to include in the labeling of these products.

V. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). 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 Regulatory 
Flexibility Act requires agencies to analyze regulatory options that 
would minimize any significant impact of a 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 by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100 million (adjusted annually for inflation) in 
any one year.
    FDA believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
The 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 Unfunded Mandates Reform Act of 1995 does not require FDA to 
prepare a statement of costs and benefits for this proposed rule, 
because the proposed 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 proposed rule is to expand an indications 
statement for OTC overindulgence drug products that contain bismuth 
subsalicylate as their active ingredient. The proposal provides 
manufacturers the option of including two additional symptoms in their 
product's indications statement. As this additional labeling is 
optional, manufacturers may elect to implement it whenever they revise 
product labeling or may elect not to include the additional information 
at all. FDA is unable to state exactly how many bismuth subsalicylate 
products have an overindulgence claim because these products may be 
marketed with other claims (e.g., for diarrhea) and not have an 
overindulgence claim. FDA's Drug Listing System (DLS) identifies 334 
OTC drug products that contain bismuth subsalicylate and are marketed 
for use

[[Page 745]]

as an antidiarrheal. Some of these products may also have a claim for 
overindulgence or may want to include a claim for overindulgence. 
Because these products could be marketed with an overindulgence claim, 
FDA is counting all such products as potentially affected by this 
proposed rule. However, because any relabeling resulting from this 
proposed rule is completely voluntary and can be done when 
manufacturers are ordering new product labeling, FDA considers any 
costs resulting from this proposed rule to be negligible. FDA 
recognizes that frequent labeling redesigns are a recognized cost of 
doing business in the OTC drug industry. Manufacturers that make 
voluntary market-driven changes to their labeling can usually do so at 
a nominal cost. FDA recognizes benefits to both manufacturers and 
consumers from this proposed labeling change. Manufacturers will have 
two additional uses for these products to promote to consumers, and 
consumers will be able to use a single product instead of two products 
(one for overindulgence and one for gas) to relieve their symptoms 
resulting from overindulgence in food and drink. FDA did not consider 
other labeling alternatives.
    This analysis shows that FDA has considered the burden to small 
entities. Therefore, FDA certifies that this proposed rule will not 
have a significant economic impact on a substantial number of small 
entities. No further analysis is required under the Regulatory 
Flexibility Act (5 U.S.C. 605(b)).

VI. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling proposed in this 
document is not subject to review by the Office of Management and 
Budget because they do not constitute a ``collection of information'' 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). 
Rather, the proposed 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)).

VII. Environmental Impact

    FDA 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.

VIII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed 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, 
FDA tentatively concludes that the proposed rule does not contain 
policies that have federalism implications as defined in the Executive 
order and, consequently, a federalism summary impact statement has not 
been prepared.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Three copies of all written comments are to be submitted. Individuals 
submitting written comments or anyone submitting electronic comments 
may submit one copy. Comments 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. Received comments may 
be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday.

X. Proposed Effective Date

    FDA is proposing that any final rule that may be issued based on 
this proposal be included in the future FM for OTC orally administered 
drug products for relief of symptoms associated with overindulgence in 
food and drink and have the same effective date as that FM.

XI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES), under Docket No. 1982N-0166 unless 
otherwise noted, and may be seen by interested persons between 9 a.m. 
and 4 p.m., Monday through Friday.
    1. FDA, ``General Guidelines for OTC Drug Combination Products, 
September 1978,'' Division of Dockets Management, Docket No. 1978D-
0322.
    2. The Procter & Gamble Co., ``In-vitro Foam Reducing Capacity 
Test: Pepto-Bismol With Simethicone,'' in C12.
    3. Lukacovic, M. F. and K. J. Watters, ``Dog Bioavailability Study 
With Pentagastrin--Pepto-Bismol With Simethicone, PBDB 14,'' 
The Procter & Gamble Co., in C12, 1992.
    4. Lukacovic, M. F. and K. J. Watters, ``Rat Gastric Lesion Study-
Pepto-Bismol With Simethicone. EtOH Study--ANTR 53,'' The 
Procter & Gamble Co., in C12, 1991.
    5. Comment 31-11370, Division of Dockets Management, Docket No. 
1978N-0263.
    6. ``Study PD 0292-07,'' The Procter & Gamble Co., in C12.
    7. Newsom, J. H., ``Evaluation of Bismuth Subsalicylate in 
Relieving Symptoms of Indigestion,'' OTC Vol. 170208 (pp. 15-17).
    8. Berkowitz, J. M., ``Bismuth Subsalicylate in Excessive Alcohol/
Food Intake,'' OTC Vol. 170208 (pp. 11-15).
    9. Hailey, F. J. and J. H. Newsom, ``Evaluation of Bismuth 
Subsalicylate in Relieving Symptoms of Indigestion,'' Archives of 
Internal Medicine, 144:269-272, 1984.
    10. Stedman's Medical Dictionary, 25th ed., Williams & Wilkins, 
Baltimore, MD, s.v. ``indigestion,'' 1990.
    11. Dorland's Illustrated Medical Dictionary, 28th ed., W. B. 
Saunders Co., Philadelphia, PA, 1994.

List of Subjects in 21 CFR Part 357

    Labeling, Over-the-counter drugs, Reporting and recordkeeping 
requirements.

0
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 357, as proposed in the Federal Register of 
December 24, 1991 (56 FR 66742), be amended as follows:

PART 357--MISCELLANEOUS INTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE

0
1. The authority citation for 21 CFR part 357 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
    2. Section 357.903 is amended by revising paragraph (a) to read as 
follows:


Sec.  357.903  Definitions.

* * * * *
    (a) Upset stomach due to overindulgence in food and drink. A 
condition that occurs as a result of overindulgence in food and drink 
and consists of a group of symptoms that includes heartburn, nausea, 
fullness, belching, and gas.
* * * * *

0
3. Section 357.950 is amended by revising paragraph (b)(2) to read as 
follows:

[[Page 746]]

Sec.  357.950  Labeling of drug products for the relief of symptoms of 
upset stomach due to overindulgence in food and drink.

* * * * *
    (b) * * *
    (2) ``For the relief of upset stomach associated with'' (select one 
or more of the following: ``nausea,'' ``heartburn,'' ``fullness,'' 
``belching,'' and ``gas'') ``due to overindulgence in food and drink.''
* * * * *

    Dated: December 15, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-154 Filed 1-4-05; 8:45 am]

BILLING CODE 4160-01-S