[Federal Register Volume 68, Number 74 (Thursday, April 17, 2003)]
[Rules and Regulations]
[Pages 18869-18882]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-9380]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 335, and 369

[Docket No. 78N-036D]
RIN 0910-AA01


Antidiarrheal Drug Products for Over-the-Counter Human Use; Final 
Monograph

AGENCY: Food and Drug Administration.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
in the form of a final monograph establishing conditions under which 
over-the-counter (OTC) antidiarrheal drug products (to control the 
symptoms of diarrhea) are generally recognized as safe and effective 
and not misbranded. This final rule is part of FDA's ongoing review of 
OTC drug products. FDA is issuing this final rule after considering 
public comments on the agency's proposed regulation, which was issued 
in the form of a tentative final monograph (TFM), and all new data and 
information on OTC antidiarrheal drug products that have come to the 
agency's attention. Also, this final rule amends the regulation that 
lists nonmonograph active ingredients by adding those OTC antidiarrheal 
active ingredients that have been found to be not generally recognized 
as safe and effective.

DATES: Effective Date: This rule is effective April 19, 2004.
    Compliance Dates: The compliance date for products with annual 
sales less than $25,000 is April 18, 2005. The compliance date for all 
other OTC antidiarrheal drug products is April 19, 2004.
    Comment Date: Comments on specific labeling items discussed in 
section IX of the SUPPLEMENTARY INFORMATION section

[[Page 18870]]

of this document are due by July 16, 2003.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Mary S. Robinson 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 March 21, 1975 (40 FR 12902), 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 
antidiarrheal drug products, together with the recommendations of the 
Advisory Review Panel on OTC Laxative, Antidiarrheal, Emetic, and 
Antiemetic Drug Products (the panel), which evaluated these drug 
classes. The agency's proposed regulation for OTC antidiarrheal drug 
products was published in the Federal Register of April 30, 1986 (51 FR 
16138), in the form of a TFM. In the Federal Register of November 7, 
1990 (55 FR 46914), the agency issued a final rule establishing that 
certain active ingredients, including some antidiarrheal active 
ingredients, in OTC drug products are not generally recognized as safe 
and effective or are misbranded. These antidiarrheal active ingredients 
are listed in Sec.  310.545(a)(3) (21 CFR 310.545(a)(3)). This final 
rule adds nine ingredients to that section.
    On or after the compliance dates established in this final rule 
(see DATES section) no OTC drug product that is subject to this final 
rule 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 new drug application 
(NDA) or abbreviated new drug application. Further, any OTC drug 
product subject to this final rule that is repackaged or relabeled 
after the effective date of the final rule must be in compliance with 
the monograph regardless of the date the product was initially 
introduced or initially delivered for introduction into interstate 
commerce. Manufacturers are encouraged to comply voluntarily with the 
conditions in this final monograph as soon as possible.
    In the TFM (51 FR 16138 at 16148), the agency proposed monograph 
status for activated attapulgite, calcium polycarbophil, and 
polycarbophil. The agency has reevaluated the data for these 
ingredients and classified them as nonmonograph conditions (see section 
III of this document). Kaolin and bismuth subsalicylate were category 
III (see Sec.  330.10(a)(6)(iii)) in the TFM. They are monograph 
conditions in this final rule.
    In the Federal Register of March 17, 1999 (64 FR 13254), the agency 
established a standardized format and content for the labeling of all 
OTC drug products (see Sec.  201.66 (21 CFR 201.66)). The labeling in 
this final monograph incorporates those requirements. The agency is 
specifically soliciting comments on the labeling for bismuth 
subsalicylate and kaolin. If the comments justify a change, the agency 
will propose to amend the final monograph accordingly at a later date.
    All ``OTC Volumes'' cited throughout this document refer to 
information on public display in the Dockets Management Branch (see 
ADDRESSES).

II. The Agency's Conclusions on the Comments

    (Comment 1) One comment requested the agency to increase the 
proposed dose for activated attapulgite (51 FR 16138 at 16149) from a 
maximum of 8.4 grams (g) per day to a maximum of 9 g per day for adults 
and children 12 years of age and over. The comment also recommended 
higher daily doses for children under 12 years old. The comment 
submitted three clinical studies to support these higher doses (Refs. 
1, 2, and 3).
    The agency has determined that the studies are insufficient to 
support an increase in the daily dose. The studies were neither 
designed nor analyzed to support the requested increase of the maximum 
daily dose. The data do not provide information as to the basis or need 
for an increased dose, do not establish a target population for such a 
dose, and do not directly compare the two dose levels in order to 
establish that the higher dose is as safe and provides any additional 
benefit. The agency's detailed comments and evaluation of the studies 
are on file in the Dockets Management Branch (Ref. 4). Moreover, based 
on a reevaluation of the studies submitted to support the effectiveness 
of attapulgite (51 FR 16138 at 16142), the agency concludes that 
additional effectiveness data are needed to support monograph status 
(see section III of this document).
    (Comment 2) One comment submitted a safety study (Ref. 5) and two 
clinical studies (Refs. 6 and 7) to support the use of bismuth 
subsalicylate for the prophylaxis of travelers' diarrhea.
    The agency has determined that the data are insufficient to support 
use of bismuth subsalicylate for prophylaxis of travelers' diarrhea. 
The safety study (Ref. 5) evaluated a dose that was 50 percent higher 
and given for a time period that was 50 percent longer than planned for 
the travelers' diarrhea study, which was a 17-week, double-blind, 
parallel, randomized study conducted in 93 healthy, adult volunteers. 
One objective was to determine the blood levels and urinary excretion 
of bismuth resulting from long-term dosing. Average blood bismuth 
concentration, after 6 weeks of dosing, was significantly higher for 
the bismuth subsalicylate four times a day group than the two times a 
day group. Blood levels slowly decreased through a 9-week followup 
period. None of the subjects in either placebo group exhibited a 
detectable blood bismuth level.
    One clinical study (Ref. 6) was a 14-day double-blind, randomized, 
placebo-controlled comparison of the prophylactic effects of two doses 
of bismuth subsalicylate on the incidence of travelers' diarrhea in 390 
subjects traveling to destinations where the incidence of travelers' 
diarrhea was at least 20 percent. Depending upon the group assigned, 
subjects were given either 525 milligrams (mg) bismuth subsalicylate 
two times a day (low dose), 1,050 mg bismuth subsalicylate two times a 
day (high dose), or lactose placebo tablets two times a day.
    The primary efficacy parameter was the incidence rate of travelers' 
diarrhea. The investigators concluded that both doses provide a 
statistically significant reduction in the occurrence of diarrhea. 
Additional analyses were done. In one analysis, the data were evaluated 
strictly according to the inclusion/exclusion criteria and the 
definition of diarrhea as stated in the protocol. Results indicated 
that the significant advantage of each dose regimen claimed in the 
original analyses was not maintained. A further (intent-to-treat) 
analysis was done using all subjects, i.e., inclusion/exclusion 
criteria were ignored and all subjects were included. This evaluation 
also did not confirm the statistical advantage of each dose regimen 
claimed in the original analysis. In addition, this study is inadequate 
because there was a 47 percent rate of protocol violations and 
differences in definitions of diarrhea used (in the protocol and in the 
evaluable subjects) raise questions about the adequacy of the blinding 
of the study.

[[Page 18871]]

    The other clinical study (Ref. 7) was a 21-day, double-blind, 
randomized, placebo-controlled clinical study comparing two dose levels 
of bismuth subsalicylate in the prevention of travelers' diarrhea. 
Subjects were randomly assigned bismuth subsalicylate either 1.05 g per 
day (262.5 mg four times a day) (low dose)), 2.1 g per day (525 mg four 
times a day) (high dose)), or 7.15 g lactose (two placebo tablets four 
times a day). Additional analyses were also done. In the original 
analysis, the difference in diarrheal incidence rate from placebo was 
only statistically significant for the high-dose regimen. Supplemental 
comparisons done only for subjects who completed all 21 days of the 
study or who contracted diarrhea (``four or more unformed stools in a 
24-hour period'') were consistent with the primary efficacy 
comparisons. The investigators concluded that 525 mg bismuth 
subsalicylate four times a day provides a statistically significant 
reduction in the occurrence of diarrhea for up to 3 weeks and that 
262.5 mg four times a day provides a marginal benefit that could be 
considered in the range of the minimum effective dose. However, this 
significant reduction in the incidence of diarrhea was not discernible 
when the data from both analyses were evaluated. Similarly, when the 
effects of the ``high'' and ``low'' bismuth subsalicylate dose were 
compared, no significant difference in the incidence of diarrhea was 
detected.
    Only the second clinical study (Ref. 7) showed that bismuth 
subsalicylate tablets in a dosage of 525 mg four times a day may be 
effective in the prevention of travelers' diarrhea. However, an 
additional double-blind, randomized, placebo-controlled study by 
another independent investigator is needed to substantiate the study 
findings. The agency's detailed comments and evaluation of the data are 
on file in the Dockets Management Branch (Ref. 8).
    The agency is concerned about the benefit-to-risk ratio associated 
with prophylactic use for several weeks for acute diarrhea, which 
itself is usually self-limiting, lasting only from 24 to 72 hours. 
Although there have been no reported cases of bismuth encephalopathy 
associated with the dosage and time period usually recommended for OTC 
use, the safety of prophylactic use for 3 weeks to persons traveling to 
high-risk diarrhea areas is not well documented. Thus, any future study 
of effectiveness should also include an evaluation of tinnitus and 
other subtle and mild central nervous system symptomatology, such as 
vertigo, gait disturbances, etc. An evaluation of bismuth 
pharmacokinetics during the period of use would also be desirable.
    (Comment 3) One comment submitted four clinical studies (Refs. 9 
through 14) to support the use of bismuth subsalicylate for the 
treatment of diarrhea for the three labeling indications discussed in 
the proposal (51 FR 16138 at 16140 to 16141). The comment also 
requested that a travelers' diarrhea claim for bismuth subsalicylate be 
included in the final monograph.
    The agency has determined that these studies (DuPont, Steffen-
DuPont, Steffen, and Gryboski) support the use of bismuth subsalicylate 
to treat the symptoms of acute nonspecific diarrhea and, tentatively, 
travelers' diarrhea. The DuPont and Steffen-DuPont studies were double-
blind, randomized, parallel group trials comparing the efficacy of 
bismuth subsalicylate with placebo for the treatment of acute, 
nonspecific diarrhea. The DuPont study (Ref. 10) involved 112 students 
from the United States enrolled at universities in Mexico and who were 
suffering from diarrhea. The subjects received placebo or bismuth 
subsalicylate at a dose of 525 mg per 30 milliliter (mL) solution every 
half hour up to a maximum of eight doses (4.2 g) per day for 2 days. 
The students were given diary cards on which to record the time of 
passage of each stool, the stool consistency, the severity of any 
associated symptoms, and the times and amounts of medication ingested. 
Diary cards were maintained for 72 hours (the 48-hour treatment period 
and the ensuing 24 hours). Diarrhea was defined as one or more symptoms 
of enteric infection (e.g., fever, abdominal discomfort, urgency, 
nausea) plus either three or more unformed stools in an 8-hour period 
or four or more such stools in a 24-hour period.
    The primary effectiveness measures were reduction in the duration 
of diarrhea, improvement in stool consistency, and reduction of stool 
frequency. Results significantly favoring bismuth subsalicylate were 
obtained for all parameters of effectiveness. Half of the subjects who 
took bismuth subsalicylate experienced total relief by 27 hours. 
Additionally, 78 percent of the subjects treated with bismuth 
subsalicylate had total relief of diarrhea and all associated symptoms 
at the end of the 72-hour period compared with 50 percent of the 
placebo-treated subjects. The mean percentage of total firm stools 
among subjects treated with bismuth subsalicylate was numerically 
greater than for the placebo-treated subjects at all time intervals, 
and significantly greater for the first 24 hours after treatment (36.6 
percent versus 8.6 percent, p<0.01). Stool frequency data also showed 
that the number of unformed stools was numerically lower for all time 
intervals after the first 12 hours for the bismuth subsalicylate 
subjects compared to the placebo subjects. However, only the 12- to 24-
hour interval showed statistical significance (p=0.04). Subjects global 
assessment of relief was 92 percent for those who received bismuth 
subsalicylate compared to 73 percent for those who received placebo on 
day 1 (p=0.032) and 98 percent versus 86 percent on day 2 (p=0.059). 
The physician's global ratings showed relief in 84 percent of subjects 
treated with bismuth subsalicylate and 58 percent of placebo subjects 
(p<0.01).
    The Steffen-DuPont study (Ref. 10) included 130 Swiss nationals 
traveling in West Africa. It had essentially the same design as the 
DuPont study except that diarrhea was defined as one or more watery 
stools (pourable) or one or more pasty stools (do not retain shape). 
Subjects were given bismuth subsalicylate 1.05 g every hour up to a 
maximum of four doses (4.2 g) per day for 2 days, or placebo. Results 
indicated that 69 percent of subjects treated with bismuth 
subsalicylate had relief after 48 hours compared to 40.6 percent for 
placebo subjects. Stool consistency was numerically higher for subjects 
treated with bismuth subsalicylate than subjects who received placebo. 
Subject's global assessments of relief was 76 percent for those who 
received bismuth subsalicylate and 72 percent for those who received 
placebo on day 1 (p=0.76). On day 2, a significantly greater percentage 
of subjects treated with bismuth subsalicylate reported relief (89 
percent) compared to placebo subjects (73 percent), p=0.02.
    A subgroup analysis on subjects identified as having entry criteria 
(three or more unformed stools before entry) similar to subjects in the 
Dupont study allowed for direct comparisons of these two studies. The 
analysis confirmed a significant effect for bismuth subsalicylate over 
placebo.
    The Gryboski study (Refs. 9 and 10) was a double-blind, placebo-
controlled, parallel clinical trial, conducted for 7 days, that 
involved 29 infants and children (age range 2 to 70 months) with 
chronic diarrhea, defined as a change in the consistency of the stool 
to watery or soft (mushy) and of greater than 2 weeks duration. A 
bismuth subsalicylate suspension containing 525 mg/30 mL was given 
based on age as follows: 6 weeks to 2 years, 2.5 mL; 2 to 6 years, 10 
mL. The results indicated that bismuth subsalicylate significantly

[[Page 18872]]

improved stool consistency and decreased stool frequency (p<0.05). 
However, because of the small sample size and because only one child 
was more than 3 years of age, this study alone cannot be used to 
establish dosages for infants and children.
    In the Steffen study (Refs. 9 and 10), 2,580 people traveling to 
various third world countries were randomly assigned in a double-blind 
manner to bismuth subsalicylate (or 1 of 5 other active drugs) or 1 of 
6 respective placebos. Treatment for diarrhea began immediately after 
the onset of symptoms. The study results, for 530 evaluable subjects, 
indicated that the cure rates for subjects treated with bismuth 
subsalicylate were 62 percent by the end of day 1 and 76 percent by the 
end of day 2, p=0.002 (Ref. 10). These rates were significantly greater 
than those in the placebo group (40 percent day 1, 55 percent day 2). 
While this study is supportive, the agency cannot consider it a 
critical study to support effectiveness for bismuth subsalicylate for 
several reasons: (1) The study did not provide baseline data, (2) the 
study did not contain objective measures of stool frequency and 
consistency, and (3) the raw data were not available to the agency for 
review.
    In summary, the Dupont and the Steffen-Dupont studies support the 
monograph status of bismuth subsalicylate for OTC antidiarrheal use. 
Each study confirms the results of the other because of the similar 
design. The Steffen study is supportive. The Gryboski study, although 
well-controlled and supportive of bismuth subsalicylate, does not 
provide adequate information on dosing regimens for children under 12 
years of age (see section II, comment 6 of this document).
    The dosage for bismuth subsalicylate is: Adults and children 12 
years of age and over: oral dose is 525 mg every 1/2 to 1 hour, or 
1,050 mg every hour as needed, not to exceed 4,200 mg in 24 hours. 
Children under 12 years of age: ask a doctor.
    Because almost 50 percent of persons traveling from an 
industrialized to an underdeveloped country experience diarrhea, this 
target population was used in the clinical studies. The primary 
etiology of diarrhea in the United States is nonbacterial, while 
diarrhea occurring in foreign countries is primarily bacterial. Thus, 
the agency needed to consider whether studies on travelers' diarrhea (a 
subset of diarrhea) in foreign countries could be extrapolated to acute 
nonspecific diarrhea in the United States (Ref. 15).
    On July 26, 1991, the agency's Gastrointestinal Drugs Advisory 
Committee considered this question by evaluating the pathogens 
identified in the restudy stool samples in the Dupont and Steffen 
studies. The most common pathogen was Escherichia coli enterotoxin. The 
committee also considered the Gryboski study, in which the entry 
criteria included subjects with no evidence of parasitic or bacterial 
infection, and the Soriano study (Ref. 15), an additional study (not 
submitted by the comment) that was conducted in hospitalized children 
with acute diarrhea and focused on subjects infected with Rotavirus. 
The Soriano study showed that bismuth subsalicylate is superior to 
placebo and is also effective in subjects with diarrhea when the 
primary etiology is viral. The committee concluded that the studies 
support the use of bismuth subsalicylate in treating the symptoms of 
acute nonspecific and travelers' diarrhea.
    In the TFM (51 FR 16138 at 16149), the agency proposed the 
following indications in Sec.  335.50(b): (i) ``Reduces the number of 
bowel movements in diarrhea,'' (ii) ``Improves consistency of loose, 
watery bowel movements in diarrhea'' and (iii) ``Relieves cramps in 
diarrhea.'' The agency also stated (see comment 10, 51 FR 16138 at 
16140 to 16141) that the indications ``For the treatment of diarrhea'' 
or ``Controls (stops) diarrhea'' could also be used depending on the 
results of studies conducted on the ingredients present in a product, 
but these indications were not included in proposed Sec.  335.50(b) 
(also, see section II, comment 13 of this document). The agency 
concludes that the data support monograph status for these claims for 
bismuth subsalicylate with the exception of ``relieves cramps in 
diarrhea.'' The data support the term ``controls'' or ``relieves'' 
rather than the absolute cessation of diarrhea inferred in the term 
``stops.'' Therefore, the agency is using the claim ``controls'' or 
``relieves'' ``diarrhea'' as the primary indication in this final 
monograph. To further simplify labeling, the agency had revised the 
other claims, which are optional, to ``reduces number of bowel 
movements'' and ``helps firm stool'' (see new Sec.  335.50(b)(1)).
    FDA tentatively concludes that the data also support use for 
``travelers' diarrhea.'' Elsewhere in this issue of the Federal 
Register, the agency is proposing to amend the final monograph to 
include that indication. However, that indication may not appear in 
product labeling until the amendment is final. The agency's detailed 
comments and evaluation of the data are on file in the Dockets 
Management Branch (Ref. 16).
    (Comment 4) One comment disagreed with an agency recommendation 
(Ref. 16) that the Reye's syndrome warning for products containing 
bismuth subsalicylate read: ``WARNING: Children and teenagers who have 
or are recovering from chicken pox or flu should NOT use this medicine 
to treat vomiting or diarrhea. If vomiting or diarrhea is present, 
consult a doctor because this could be an early sign of Reye syndrome, 
a rare but serious illness.'' The comment contended that this reference 
to diarrhea should not be included because, unlike vomiting, diarrhea 
is not a recognized early warning symptom of Reye's syndrome. The 
comment added that this warning would be incorrect and confusing to 
consumers and that there is no scientific data linking Reye's syndrome 
to bismuth subsalicylate. One comment added that the following Reye's 
syndrome warning it voluntarily uses in its labeling is adequate for 
bismuth subsalicylate: ``WARNING: Children and teenagers who have or 
are recovering from chicken pox or flu should not use this medicine to 
treat nausea or vomiting. If nausea or vomiting is present, consult a 
doctor because this could be an early sign of Reye Syndrome, a rare but 
serious illness.''
    FDA issued the Reye's syndrome warning in 21 CFR 201.314(h) at the 
time when scientific research was focused primarily on the association 
of Reye's syndrome and aspirin rather than nonaspirin salicylates. That 
warning is limited to aspirin and reads: ``WARNING: Children and 
teenagers should not use this medicine for chicken pox or flu symptoms 
before a doctor is consulted about Reye's syndrome, a rare but serious 
illness reported to be associated with aspirin.''
    In the Federal Register of May 5, 1993 (58 FR 26886), the agency 
proposed a Reye's syndrome warning for OTC overindulgence drug products 
containing bismuth subsalicylate. In a technical amendment published in 
the Federal Register of January 3, 2000 (65 FR 7), the agency corrected 
the word ``Reye'' to ``Reye's.'' Elsewhere in this issue of the Federal 
Register, the agency is finalizing the May 5, 1993, proposal, requiring 
the Reye's syndrome warning for all OTC drug products that contain 
bismuth subsalicylate.
    (Comment 5) One comment disagreed with the agency's proposal (51 FR 
16138 at 16143, see comment 17) that the maximum adult daily dose of 
bismuth subsalicylate be limited to 4.2 g because of the potential of 
salicylate toxicity. The comment argued that this limitation is 
contrary to the up to 8 g per 1 day

[[Page 18873]]

limit of bismuth subsalicylate recommended by the panel (40 FR 12902 at 
12930). The comment stated that 4.2 g per day is equivalent to 1.59 g 
per day salicylate, which is only about one-half of the maximum daily 
salicylate dosage limit recommended by the OTC Internal Analgesic Panel 
(42 FR 35346 at 35358, July 8, 1977).\1\ The comment stated that it is 
essential that the maximum allowable dose be based on total salicylate 
consumption because some bismuth subsalicylate products may also 
contain other salicylates as excipients. Thus, the maximum daily dose 
should be limited by the equivalents of salicylate ingested, and that 
formulated products should contain a total of no more than 3.04 g of 
salicylate per day. The comment stated that the bismuth subsalicylate 
level should be established by the lowest clinically effective dose.
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    \1\The panel's recommended maximum daily dosage for sodium 
dalicylate was 4 g. Sodium salicylate contains approximately 14 
percent sodium and 86 percent salicylate. Four g of sodium 
dalicylate contains approximately 3.4 g of salicylate.
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    Based on clinical studies submitted (see section II, comment 3 of 
this document), bismuth subsalicylate for antidiarrheal use has been 
shown to be effective at a dose of 4.2 g per day. Thus, there is no 
rationale for increasing the daily dosage to up to 8 g. The agency is 
aware that products may contain other salicylates as excipients 
(formulation aids). Inactive ingredients must meet the requirements of 
Sec.  330.1(e) (21 CFR 330.1(e)), i.e., be safe and not interfere with 
the effectiveness or testing of the product. There is no basis at this 
time to place a restriction on the use of other salicylates as inactive 
ingredients. However, manufacturers would be prudent to use 
nonsalicylate inactive ingredients when bismuth subsalicylate is the 
active ingredient. The agency will consider a restriction should the 
need arise.
    (Comment 6) One comment submitted a report (Ref. 17) from a 
Scientific Advisory Group (SAG) that evaluated pediatric dosing for 
bismuth subsalicylate. The SAG reviewed three studies (Refs. 18, 19, 
and 20) and marketing and epidemiological data. The SAG report 
concluded that: (1) The clinical data support the safety and 
effectiveness of bismuth subsalicylate to treat diarrhea in children 
between 3 and 12 years of age, (2) currently recommended dose regimens 
to treat diarrhea in children 6 to 12 years of age, based on the 
effective adult dose of bismuth subsalicylate, are rational and 
supportable. However, increasing the currently marketed labeled dose 
for children 3 to 6 years old is recommended, (3) no additional 
clinical studies are required to treat acute diarrhea in children 3 to 
12 years old, and (4) bismuth subsalicylate labeling should include a 
warning to maintain adequate fluid intake when treating diarrhea in 
young children.
    Based on the SAG's recommendations, the comment requested an age 
range and dosage schedule different from that included in the TFM. The 
comment stated that its age ranges were intended to be consistent with 
the age ranges specified in pediatric dose schedule C of the advance 
notice of proposed rulemaking for OTC internal analgesic, antipyretic, 
and antirheumatic drug products (42 FR 35346 at 35368). The comment 
explained that age groupings in that monograph were determined on the 
basis of body surface area, which, according to the Internal Analgesic 
Panel, is the most accurate parameter to use in calculating salicylate 
dosage. The SAG stated that the pediatric dosages on currently marketed 
bismuth subsalicylate containing products are rational for children 
ages 6 to 9 and 9 to 12 years of age. Employing extrapolations based on 
age (Young's rule), body-weight, and body-surface area from an 
effective adult dose, the SAG recommended an increase in the dose for 
children 3 to 6 years of age from the currently-labeled dose of 87 mg 
to 131 mg.
    The agency has reviewed the SAG report, which discusses three 
controlled studies (Refs. 18, 19, and 20) in infants and children (8 
weeks to under 5 years) with chronic or acute diarrhea. However, only 
one subject was above 3 years of age. The comment contended these 
studies were sufficient evidence to show effectiveness in childhood 
diarrhea at various doses. The doses of bismuth subsalicylate used 
were: (1) Gryboski study (chronic diarrhea) (Ref. 18): 44 mg every 4 
hours for 7 days for infants from 8 weeks to 2 years of age (mean 5.7 
mg/kilogram (kg)) and 88 mg every 4 hours for 7 days for children 2 to 
6 years of age (only 1 subject in this study was above 3 years of age, 
5.5 mg/kg); (2) Soriano-Brucker et al. study (Ref. 19): 20 mg/kg five 
times a day for 5 days, and (3) Figueroa et al. study (Ref. 20): 20 mg/
kg and 30 mg/kg five times a day for 5 days. Because these studies did 
not include children 3 to under 12 years of age, the agency has no 
basis to conclude from these studies that the ingredient will be 
effective for these age groups. The agency's detailed comments and 
evaluation of the data are on file in the Dockets Management Branch 
(Ref. 21).
    Another comment included the results of a double-blind, placebo 
controlled study of bismuth subsalicylate in children 3 to 6 years of 
age with acute diarrhea (Ref. 22). The study involved children from 13 
clinical centers located in Central and South America and the United 
States. Subjects were randomized to receive 131 mg bismuth 
subsalicylate or matching placebo every 30 minutes for a total of eight 
doses per day for 2 consecutive days. Observations were recorded in a 
diary over a 5-day period. Subjects were eligible if they had diarrhea 
of less than 48 hours in duration. Efficacy parameters included 
duration of diarrhea (primary variable), stool consistency and 
frequency (secondary variables). A total of 291 patients were included 
in the final analysis. The study demonstrated that subjects receiving 
bismuth subsalicylate showed a statistically significant shorter 
duration of diarrhea versus placebo when evaluated at 72 hours (LR 
(likelihood ratio) p=0.009) and 120 hours (LR p=0.001), but statistical 
significance was not shown at 48 hours (LR p=0.228). The p-values were 
calculated via the likelihood ratio test for comparing equality of 
survival curves. The comment stated that the shorter observation period 
of 48 hours contained more censored observation times and hence had 
less statistical power to detect the treatment effect than that at 72 
hours.
    The agency considers it reasonable to expect efficacy to be shown 
at 120-hours due to the self-limited nature of nonspecific diarrhea. 
However, failure to demonstrate a statistically significant effect at 
48-hours is a cause for concern in the pediatric population due to the 
danger that dehydration poses to this age group. Analysis of the 
secondary variables, stool consistency and frequency, revealed that 
while subjects treated with bismuth subsalicylate as compared to those 
treated with placebo had a statistically significant increase in the 
number of formed stools at the 36 to 48 hour time interval, they only 
demonstrated a trend towards a decrease in the frequency of unformed 
stools (defined as soft or watery bowel movements) and never achieved 
statistical significance for the entire duration (120 hours) of the 
study.
    The study was well designed to demonstrate the product's 
effectiveness as an antidiarrheal agent. On review, the majority of the 
reported protocol violations (i.e., randomization out of sequence, 
discrepancy in stool analysis, use of acetaminophen, study duration, 
and the filling out of the study diary cards) realistically should not 
have

[[Page 18874]]

negatively impacted on the study's results. The size of the doses of 
bismuth subsalicylate used in this trial may have been subtherapeutic 
(hence the lack of a demonstrable treatment effect) since they were 
extrapolated from doses that have been shown to be effective in adult 
populations for the indication that was studied in this trial. Since 
bismuth subsalicylate's proposed antidiarrheal efficacy stems from 
various mechanisms (anti-infective, absorbent, and antisecretory) that 
work locally in the gastrointestinal tract, the product may not have 
had adequate time or surface area to work effectively in the pediatric 
subjects tested.
    The agency concludes that another double-blind, placebo-controlled 
study in pediatric subjects with acute nonspecific diarrhea is needed 
to support the use of bismuth subsalicylate for OTC antidiarrheal use 
in children under 12 years of age. The agency recommends dose ranging 
studies using pharmacokinetic modeling to determine the doses to be 
used in the next trial. Accordingly, labeling for use in children 3 to 
under 12 years of age is not included in the monograph at this time.
    (Comment 7) Two comments stated that it is generally recognized 
that the therapeutic value in bismuth salts is dependent on the 
percentage of bismuth oxide. One comment discussed two products (one 
containing bismuth subsalicylate and the other containing bismuth 
subnitrate) and stated that the dosage of the bismuth subnitrate 
product provides 16.75 percent more bismuth oxide than the bismuth 
subsalicylate product. The second comment stated that bismuth 
subgallate contains 9.35 mg/mL (52 to 57 percent) of bismuth oxide, 
bismuth subnitrate contains 75.84 mg/mL (not less than 79 percent) of 
bismuth oxide, and bismuth subsalicylate contains 11.20 mg/mL (62 to 66 
percent) of bismuth oxide. The comment contended that bismuth 
subsalicylate at the recommended dosage is under dosed in effectiveness 
and concluded that bismuth subnitrate should be placed in category I. 
Another comment discussed the dose of bismuth subnitrate.
    The comments did not submit any data to establish the exact 
mechanism of action of bismuth oxide in treating/relieving diarrhea. 
Bismuth subgallate, bismuth subnitrate, and bismuth subsalicylate, 
although chemically similar, are not chemically identical and, 
therefore, may not exert the same intended action. No clinical data 
have been submitted to show that these other bismuth compounds are 
acceptable for OTC antidiarrheal use. Additionally, no data have been 
submitted to show that bismuth subsalicylate and bismuth subnitrate are 
therapeutically equivalent or that bismuth subnitrate is as effective, 
or more effective, than bismuth subsalicylate for use as an OTC 
antidiarrheal drug product. Therefore, the agency concludes that there 
is no basis to include bismuth subgallate or bismuth subnitrate in this 
final monograph.
    (Comment 8) One comment submitted a clinical study (Refs. 23, 24, 
and 25) and requested that activated charcoal (at a dose of 1,040 mg 
after each bowel movement (up to 8,320 mg per day)) be reclassified 
from category III to category I and included in the final monograph.
     The agency has determined that the data are inadequate to support 
effectiveness. The prospective, randomized, double-blind study (Ref. 
23) was conducted at a single center where 51 subjects having 
nonspecific gastroenteritis with diarrhea, with or without associated 
abdominal cramps, completed the study. The data showed weak trends on 
diarrhea-related endpoints and a somewhat stronger trend on the global 
endpoint. There was no statistical significance for any of the three 
measures of outcome: (1) The patients' ``global'' (subjective) 
evaluation of treatment effectiveness, (2) the time from initiation of 
treatment until the last unformed stool, and (3) the time from 
initiation of treatment until the last cramp was reported. Because 
there are no well-controlled studies showing effectiveness, most likely 
two independently-conducted, placebo-controlled clinical trials will be 
needed to confirm the effectiveness of activated charcoal for 
antidiarrheal use. The agency's detailed comments and evaluation of the 
data are on file in the Dockets Management Branch (Ref. 26).
    (Comment 9) One comment requested that a product containing a 
combination of bismuth subnitrate and calcium hydroxide be reclassified 
from category III to category I. The comment stated that the product 
has been sold in the United States since 1900 and in Mexico since 1923 
for OTC antidiarrheal use with no reports of consumer injury and 
contended that controlled studies are unnecessary because of the many 
years of usage without reported adverse side effects and the vast 
amount of material in the scientific literature. The comment explained 
that bismuth subnitrate has been used as an antidiarrheal for over 200 
years and that calcium hydroxide, an antacid and astringent, extends 
the shelf life of the product by neutralizing the acid residue that 
leaches from the bismuth subnitrate into the supernatant liquid over a 
long-standing period. The comment provided selected extracts from 
reference textbooks (Ref. 27).
    The panel classified bismuth subnitrate in category III because of 
insufficient effectiveness data and stated that it should not be used 
in infants under 2 years of age because of the risk of 
methemoglobinemia (40 FR 12902 at 12930). The panel placed calcium 
hydroxide in category III and stated that, although it is claimed 
useful for its antacid and buffering qualities, there is no evidence of 
effectiveness as an antidiarrheal (40 FR 12902 at 12930). The panel 
also stated that the combination of an antidiarrheal and an antacid is 
not rational concurrent therapy for a significant portion of the 
population and classified it as category II (40 FR 12902 at 12927 and 
12930). The panel was also unable to find evidence to demonstrate that 
astringent properties for calcium hydroxide confer effectiveness in 
diarrhea (40 FR 12902 at 12929 to 12930).
    While the absence of reported adverse reactions or historical use 
may be used as corroborative data, they cannot generally be considered 
as proof of safety or effectiveness (see Sec.  330.10(a)(4)(i) and 
(a)(4)(ii)). New relevant data can be submitted in an NDA (see 21 CFR 
part 314) or a petition to amend the final monograph (see Sec. Sec.  
330.10(a)(12) and 10.30 (21 CFR 10.30)).
    (Comment 10) Two comments requested the agency to designate rhubarb 
fluidextract and potassium carbonate as inactive ingredients instead of 
category II active ingredients in products that also included bismuth 
subnitrate and calcium hydroxide as active ingredients. The comments 
stated that rhubarb fluidextract is a necessary flavoring and coloring 
agent, while potassium carbonate causes the rhubarb fluidextract to go 
into solution. The comments added that the Panel was of the opinion 
that the potassium carbonate should be listed as an inactive ingredient 
(40 FR 12902 at 12926).
    Based on data the manufacturer submitted, the panel reviewed 
rhubarb fluidextract and potassium carbonate as single active 
antidiarrheal ingredients (40 FR 12902 at 12926) as well as in 
combination with bismuth subnitrate and calcium hydroxide (40 FR 12902 
at 12932). The manufacturer claimed that the rhubarb fluidextract is an 
astringent and that the potassium carbonate has some antacid value in 
the formulation (Ref. 28). The panel concluded that evidence was 
lacking to support effectiveness and placed the ingredients singly and 
in combination in category II. The panel stated that it found no 
evidence that potassium carbonate

[[Page 18875]]

possesses any antidiarrheal properties and, thus, it should be regarded 
as an inactive ingredient. Likewise, the panel concluded that there was 
no evidence to permit classification of rhubarb fluidextract as an 
antidiarrheal (40 FR 12902 at 12926). No data were subsequently 
submitted to support these ingredients as active ingredients. 
Therefore, in the TFM (51 FR 16138 at 16146 to 16147), the agency 
placed rhubarb fluidextract and potassium carbonate singly and in 
combination in category II. No additional data have been submitted, and 
rhubarb fluidextract and potassium carbonate are nonmonograph active 
ingredients in this final rule.
    The agency is not aware of rhubarb fluidextract or potassium 
carbonate being included as inactive ingredients in any OTC 
antidiarrheal drug products. Rhubarb garden root and rhubarb root are 
listed in 21 CFR 172.510 as flavors only in alcoholic beverages. 
Potassium carbonate is listed in 21 CFR 184.1619 as a substance 
affirmed as generally recognized as safe that may be added directly to 
human food. These ingredients would need to meet the criteria in Sec.  
330.1(e) to be acceptable inactive ingredients in products marketed 
under an OTC drug monograph.
    (Comment 11) One comment submitted 6 clinical studies (Ref. 29) to 
support the use of kaolin and pectin in a ``fixed'' combination of 45 
parts kaolin to 1 part pectin for the proposed labeling indications to 
treat diarrhea (51 FR 16138 at 16140 to 16141).
    The agency has determined that these studies are insufficient to 
demonstrate that the ``fixed'' combination is effective. However, 
studies 295 and 303 demonstrate that kaolin alone, but not pectin, is 
effective. While only these studies are summarized in this document, 
the agency's detailed comments and evaluations of all the studies are 
on file in the Dockets Management Branch (Refs. 30 and 31). Kaolin 
(26.2 g) and/or pectin (583 mg) as single ingredients, or in 
combination, were administered in a 3 ounce (oz) dose in all six 
studies.
    In study 303, acute nonspecific diarrhea was defined as the passage 
of three or more watery or mixed stools in 24 hours. In this 33-center 
study, the subjects were randomized as follows: 125 to receive kaolin 
and pectin in combination, 126 to receive kaolin, 133 to receive 
pectin, and 124 to receive placebo. Each subject received an initial 3-
oz dose of study medication, followed by a 3-oz dose every 6 hours or 
after each bowel movement, whichever was more frequent (not to exceed 
10 doses per 24 hours), for a 48-hour period or until diarrhea ended. 
From a total of 508 subjects, 414 were evaluable for effectiveness for 
both the first and second days of treatment.
    The results indicated reasonable statistical evidence that stool 
consistency is improved by kaolin and pectin in combination and kaolin 
alone. However, this study did not provide sufficient statistical 
evidence that kaolin and pectin as a ``fixed'' combination is superior 
to kaolin in terms of improving stool consistency on day 2 of 
treatment. There was no statistical evidence that pectin is effective 
in improving stool consistency.
    Treatment with both kaolin and pectin in combination and kaolin 
alone reduced the average elapsed time from first drug dose to either 
last liquid (watery or mixed) stool or first formed stool by 5 to 7 
hours (p<0.01) in comparison to placebo during the 48-hour treatment 
period. The duration of diarrhea was the time from the first dose to 
the first formed stool, which was 37 hours with kaolin and pectin in 
combination and 43 hours with placebo, a 6 hour difference over the 48-
hour duration of treatment. Neither kaolin and pectin in combination 
nor kaolin alone was superior to placebo in reducing the number of 
stools passed in the 48-hour treatment period.
    Study 295 was a multicenter, double-blind, randomized study 
comparing the effectiveness of the combination with placebo to treat 
acute nonspecific diarrhea, which was defined as the passage of three 
or more liquid stools in the 24 hours immediately preceding entry into 
the study. The study had 213 subjects (109 received drug, 104 received 
placebo) who were instructed to take one 3-oz dose of medication after 
each bowel movement or at 6 hour intervals in the absence of a bowel 
movement, for a period of 48 hours or until diarrhea ended, not to 
exceed 10 doses in 24 hours. The subjects recorded on a diary card the 
date and hour of each bowel movement and the character of the stool.
    The results showed improvement in the consistency of the stool in 
the drug group on day 2 of treatment. A statistically significant 
greater proportion of subjects receiving the combination had formed 
stools on day 2 (kaolin-pectin 51/81, 63 percent compared to placebo 
30/75, 40 percent, p<0.005). The mean time to the first formed stool 
was 35 hours with kaolin and pectin in combination and 41 hours with 
placebo (p=0.002). The difference in the mean number of watery stools 
(kaolin-pectin 0.13, placebo 0.57) was 0.44 of a stool, and the 
difference in the mean number of formed stools (kaolin-pectin 0.97, 
placebo 0.52) was 0.45 of a stool. No statistical significance was 
demonstrated for frequency of bowel movements on day 1 and day 2. 
Numerically, the placebo group had a slightly larger mean stool 
frequency at baseline, which was taken 24 hours prior to entrance into 
the study (6.65 for drug and 7.67 for placebo), but there was little 
difference in the mean number of bowel movements between the two 
treatment groups on day 1 (3.78 for drug and 3.37 for placebo) and day 
2 (2.02 for drug and 2.01 for placebo). The agency concludes that the 
combination resulted in a statistically significant improvement in the 
mean time to the first formed stool and in the consistency of the stool 
on day 2 of treatment.
    In study 303, the improvement in stool consistency appeared to be 
due to the kaolin component whereas pectin seemed to perform similar to 
placebo. Thus, the improvement in stool consistency in study 295 
appeared to be due entirely to kaolin alone. Therefore, the results 
indicate that kaolin alone improves stool consistency in a 24- to 48-
hour period. Likewise, study 303 also showed that the combination and 
kaolin alone significantly reduced the duration from first drug doses 
to either first normal (formed) stool or last loose (watery or mixed) 
stool (p<0.05) by 5 to 7 hours (compared to placebo) during the 48-hour 
treatment period. Study 295 also showed that the combination 
significantly reduced the duration from first dose to first normal 
stool (p<0.005) by 7 hours.
    The agency concludes that the evidence is not sufficient to show 
that kaolin and pectin in combination are better than kaolin alone. 
However, study 303 provides reasonable statistical evidence that kaolin 
as a single ingredient is likely to improve stool consistency in 
subjects with acute nonspecific diarrhea in 24 to 48 hours. Data from 
this and other studies have shown that pectin has no effect. Although 
study 295 involved a comparison of the combination only against 
placebo, rather than against the single ingredients, the study supports 
kaolin as the active ingredient in the combination product.
    On April 9, 1993, the Nonprescription Drugs Advisory Committee and 
the Gastrointestinal Drugs Advisory Committee (the committees) met to 
discuss OTC antidiarrheal drug products containing attapulgite, kaolin, 
and pectin (Ref. 31). The committees evaluated studies 295 and 303 and 
determined that the data were sufficient to support the effectiveness 
of kaolin as a single ingredient, recommending that

[[Page 18876]]

products be labeled to state the results they provide and the timeframe 
in which they occur. Therefore, the agency is including the following 
indication for kaolin in this final monograph: ``Helps firm stools 
within 24 to 48 hours'' (see section III of this document).
    Kaolin is an adsorbent that can interfere with the gastrointestinal 
absorption of a number of oral medications, including some antibiotics, 
digitalis glycosides, and theophylline, resulting in decreased 
therapeutic effectiveness. The interaction might be avoided if kaolin 
is given at least 3 hours before or after taking any oral medication. 
Therefore, the agency is requiring a specific drug interaction 
precaution statement for products containing kaolin: ``Ask a doctor or 
pharmacist before use if you are taking any other drugs. Try to use at 
least 3 hours before or after taking any other drugs.''
    The committees also noted that the available data did not address 
the safety and effectiveness of kaolin in children and recommended that 
the ingredient should not be administered to children under 12 year of 
age without the specific recommendations of a doctor. Further, the 
agency is concerned about use in children because they may have a 
greater potential for fluid loss and electrolyte imbalance due to 
diarrhea and antidiarrheal products that only improve stool consistency 
may mask the extent of fluid loss. Dehydration due to diarrhea in 
children can occur early in the disease process and may have serious 
consequences, such as circulatory collapse and renal failure (Ref. 32). 
Kaolin improves stool consistency in 24 to 48 hours. However, current 
information is insufficient to show whether it also reduces fluid and 
electrolyte loss. None of the studies demonstrated the effectiveness of 
kaolin in children under 12 years of age. As noted in the TFM (51 FR 
16138 at 16145), one study on the use of kaolin and pectin in children 
3 to 11 years old indicated some possible benefit for a greater number 
of formed stools and a smaller number of liquid stools from either the 
kaolin-pectin combination or pectin alone. However, because of the lack 
of sufficient information, it could not be adequately evaluated. The 
agency concludes that the available information is insufficient to 
include monograph directions for kaolin for children 3 to under 12 
years of age. Adequate data from a double-blind, placebo-controlled 
study in pediatric subjects with acute nonspecific diarrhea is needed 
to support the safety and effectiveness of kaolin for use in this age 
group.
    Based on the studies evaluated, the dosage for kaolin in this final 
monograph is: Adults and children 12 years of age and over: oral dosage 
is 26.2 g after each loose stool. Continue to take every 6 hours until 
stool is firm but not more than 2 days. Do not exceed 262 g in 24 
hours. Children under 12 years of age: ask a doctor.
    (Comment 12) One comment contended that the proposed labeling 
indications are too detailed and technical and, thus, will not be 
understood by persons of low comprehension. The comment argued that 
many users of OTC drug products have little education and take these 
products on their own without the direction of a physician, clinician, 
nurse, or pharmacist. To simplify the labeling for persons of low 
comprehension, the comment suggested that the statement of identity be 
``for diarrhea'' instead of ``antidiarrheal.'' The comment also 
suggested that the indication ``Reduces the number of bowel movements 
in diarrhea'' be changed to ``Decreases bowel movements'' or ``Reduces 
bowel movements.''
    The agency agrees. Section 335.50(a) in this final rule gives 
manufacturers the option of using either ``antidiarrheal'' or ``for 
diarrhea'' as the statement of identity for these products. The agency 
modified the indication to ``reduces number of bowel movements'' and 
included it as an additional optional claim for products containing 
bismuth subsalicylate (see section III this document).
    (Comment 13) One comment stated that there was a contradiction in 
the indications proposed in Sec.  335.50(b) (51 FR 16138 at 16149). The 
comment noted that the agency stated that it was recommending that the 
indications ``For the treatment of diarrhea'' or ``Controls (stops) 
diarrhea'' be used in the labeling of OTC antidiarrheal drug products, 
but these indications were not included in the proposed monograph (51 
FR 16138 at 16140 to 16141). The comment also suggested that ``relieves 
pain in diarrhea'' be a monograph indication. The comment stated that 
these indications are good, simple, and understandable and should be 
adopted by the agency.
    The comment is correct that the indications ``For the treatment of 
diarrhea'' or ``Controls (stops) diarrhea'' were not included in the 
TFM. In comment 10 of the TFM (51 FR 16138 at 16140 to 16141), the 
agency stated that one or more of the following indications could be 
used depending upon the results of studies conducted on the ingredient 
contained in the product: (1) ``For the treatment of diarrhea'' or 
``Controls (stops) diarrhea''; (2) ``Reduces the number of bowel 
movements in diarrhea''; and (3) ``Improves consistency of loose, 
watery bowel movements in diarrhea.'' Based on the data on attapulgite, 
calcium polycarbophil, and polycarbophil evaluated in the TFM, only the 
second and third indications were proposed at that time.
    The agency would not object to use of the indication ``relieves 
pain in diarrhea,'' provided studies support this claim. In the TFM (51 
FR 16138 at 16141), the agency stated that there are other symptoms 
that are secondary to diarrhea, such as abdominal pain or cramps, and 
that some antidiarrheal ingredients may also act to relieve these 
symptoms. However, adequate supporting data have not been submitted to 
date.
    (Comment 14) One comment requested revisions in the warning 
proposed in Sec.  335.50(c), which stated: ``Do not use for more than 2 
days, or in the presence of fever, or in children under 3 years of age 
unless directed by a doctor.'' The comment recommended: ``If diarrhea 
continues for more than 2 days or is accompanied by a fever, consult 
your doctor.'' The comment stated that the agency's proposed wording 
inappropriately suggests that consumers should be concerned about 
safety of the product if it is used for more than 2 days or in the 
presence of fever. The comment contended that its revision would alert 
consumers to the serious conditions that may be indicated by prolonged 
diarrhea or diarrhea accompanied by fever and would emphasize the need 
for medical attention because of the disease condition, not because of 
drug use, as might be inferred from the agency's proposed warning. The 
comment also recommended deletion of the part of the proposed warning 
regarding use in children under 3 years of age because it is redundant 
with information that appears in the directions section. The comment 
explained that the directions proposed in Sec.  335.50(d) advise that 
these products should not be used in children under 3 years of age 
without consulting a doctor and the professional labeling proposed in 
Sec.  335.80 provides health professionals information about using 
these products in children under 3 years of age.
    The agency agrees that the information about use in children is 
repetitious and could be deleted. The directions in Sec.  335.50(d) in 
this final monograph advise to ``ask a doctor'' for children under 12 
years of age. The final monograph does not include proposed

[[Page 18877]]

Sec.  335.80--professional labeling, because of the lack of adequate 
studies to support the safety and effectiveness of the monograph 
ingredients in children of any age.
    The OTC drug product labeling format has changed since the TFM was 
published. Under the current format, the word ``fever'' follows the 
subheading ``Ask a doctor before use if you have.'' The phrase ``Do not 
use for more than 2 days'' is now included after the subheading ``Stop 
use and ask a doctor if'' as ``[bullet] diarrhea lasts more than 2 
days.'' Because this information is now in the final monograph, the 
agency is removing the warning statement for ``DIARRHEA PREPARATIONS'' 
in Sec.  369.20 (21 CFR 369.20).
    (Comment 15) One comment noted the agency's statement that the 
following labeling might be required for bismuth subsalicylate: ``This 
product may cause the stool to darken or cause a temporary darkening of 
the tongue'' (51 FR 16138 at 16143). Although agreeing in principle, 
the comment stated that it should appear as a notation and not as a 
warning because this effect is temporary and harmless. The comment 
suggested the labeling read as follows: ``This product may cause a 
temporary, but harmless, darkening of the stool and tongue.''
    The agency agrees in part. Under the new OTC drug labeling format, 
this statement appears under the ``Warnings'' subheading ``When using 
this product'' as ``a temporary, but harmless, darkening of the stool 
and/or tongue may occur''.

III. Summary of Significant Changes From the Proposed Rule

    The agency has reclassified activated attapulgite from proposed 
category I to a nonmonograph condition in Sec.  310.545(a)(3) because 
of insufficient effectiveness data. On April 9, 1993, the committees 
discussed the continued marketing of products containing attapulgite 
(Ref. 31). They reviewed effectiveness studies (Refs. 33 through 36) 
cited in the TFM (51 FR 16138 at 16142) and reviewed two studies (Refs. 
37 and 38) not previously considered. The committees determined that 
the data were not sufficient to support the effectiveness of activated 
attapulgite for antidiarrheal use. One study (Ref. 33) was not 
implemented according to its protocol and adequate data were not 
collected or recorded in the individual patient report forms. Thus, the 
results were not considered interpretable. The committees questioned 
the method of collection and reporting of data, and the amount of 
lactose in the placebo used in another study (Refs. 35, 36, and 37). 
The results were considered questionable because lactose can cause 
diarrhea in individuals with lactase deficiency. The committees 
concluded that replication of the study results by an independent 
investigator was needed.
    The two new studies (Refs. 37 and 38) were active treatment-
controlled, comparing attapulgite with loperamide. The authors of one 
study (Ref. 37) stated that the results of this bicentric, randomized, 
parallel-group, comparative study showed that attapulgite was as 
effective as loperamide in stopping diarrhea. They concluded that 
attapulgite offers the safety of a nonsystemic adsorbent while 
providing efficacy equivalent to that of loperamide, a systemic 
antiperistaltic drug. However, the committees determined that, because 
of the absence of a placebo control, the authors' conclusions indicated 
a value judgment and no conclusions of efficacy could be determined 
from the study. The results of the other study (Ref. 38), a randomized, 
parallel, open-label study, suggested that loperamide, the active 
treatment-control, was better than attapulgite. Because no placebo 
control was used, the committees felt that no decision could be made as 
to the effectiveness of attapulgite in stopping diarrhea.
    While acknowledging that FDA's ``Guidelines for the Clinical 
Evaluation of Antidiarrheal Drugs'' (Ref. 39) indicate that a reference 
drug of proven efficacy may be used, the committees stated that 
improvement could be shown with any drug because the duration of 
symptoms of acute nonspecific diarrhea is 2 days. Therefore, it was the 
committees' consensus that placebo-controlled studies were needed to 
establish the effectiveness of attapulgite.
    FDA notified the OTC drug manufacturers association by 
correspondence dated September 14, 1993, of the agency's intent to 
classify attapulgite as a nonmonograph condition (Ref. 40). The agency 
requested interested parties to submit any additional data on these 
ingredients in the form of a petition to reopen the administrative 
record. FDA placed this correspondence in the public docket, but has 
not received any additional data or other comments in response to its 
request. Thus, based on the above analysis and the recommendation of 
the committees, FDA has classified this ingredient as a nonmonograph 
condition in this final rule.
    The agency has reclassified bismuth subsalicylate from category III 
to a monograph condition in Sec.  335.10(a) (see section II, comment 3 
of this document) and included specific labeling in Sec.  335.50(b)(1), 
(b)(3)(ii), (c)(2), and (d)(2) for products containing bismuth 
subsalicylate (see section II, comments 3, 4, 5, and 15 of this 
document).
    The agency has reclassified calcium polycarbophil and polycarbophil 
from proposed category I to a nonmonograph condition in Sec.  
310.545(a)(3) because of insufficient effectiveness data. On April 9, 
1993, the committees discussed the continued marketing of OTC 
antidiarrheal drug products containing attapulgite, kaolin, and pectin 
(Ref. 31). Based on the effectiveness issues the committees raised, the 
agency rereviewed the data cited in the TFM (51 FR 16138 at 16141 to 
16142) and determined that the existing data do not support the OTC use 
of calcium polycarbophil and polycarbophil for acute nonspecific 
diarrhea (Refs. 40 and 41). Only two of the studies relied on by the 
panel (40 FR 12926) and the agency (51 FR 16138 at 16141) to support 
monograph status involved subjects with acute nonspecific diarrhea 
(Refs. 42 and 43). These studies were conducted in a population in 
which the majority (88 to 92 percent) of subjects enrolled were less 
than 5 years old. No placebo controls were used and the comparative 
drug (kaolin-pectin suspension) had not been shown to be effective at 
the time of the trial. There was no indication of duration of diarrhea 
preceding treatment or relationship to onset of relief, and the 
randomization scheme was unequal and unclear. The agency does not 
believe that these data can be extrapolated to an adult population.
    The other studies previously cited in support of polycarbophil 
included an uncontrolled study (Ref. 44) on the effectiveness of 
polycarbophil for the relief of constipation, a condition not covered 
in this monograph. Two other studies (Refs. 45 and 46) are inadequate 
because chronic diarrhea was considered, the patient selection criteria 
were not defined, and concomitant medications were unknown.
    Therefore, the agency has classified calcium polycarbophil and 
polycarbophil as nonmonograph conditions. Placebo-controlled studies 
are needed to establish their effectiveness. FDA notified the OTC drug 
manufacturers association by correspondence dated May 5, 1994, of the 
agency's intent to classify calcium polycarbophil and polycarbophil as 
nonmonograph conditions (Ref. 41). FDA requested interested parties to 
submit any additional data concerning these ingredients to the agency. 
FDA placed this correspondence in the public docket, but has not 
received any

[[Page 18878]]

additional data or other comments in response to its request. New 
relevant data can be submitted in accordance with Sec. Sec.  
330.10(a)(12) and 10.30.
    For products containing bismuth subsalicylate, a required 
indication is included in Sec.  335.50(b)(1) as follows: ``The labeling 
states [select one of the following: ``controls'' or ``relieves''] 
``diarrhea''. Additional indications'' in Sec.  335.50(b)(3)(ii)'' * * 
* include one or both of the following * * *: ``[bullet] reduces number 
of bowel movements'' ``[bullet] helps firm stool''.'' The indication 
``Relieves pain in diarrhea'' has not been included because of 
insufficient data to support such a claim (see section II, comment 12 
of this document).
    The agency is including in new Sec.  335.50(b)(2) the following 
indication for kaolin: ``helps firm stool within 24 to 48 hours'' (see 
section II, comment 11 of this document).
    The agency has revised the warnings included in the TFM (see 
section II, comments 4, 14, and 15 of this document).
    Because the potential for fluid loss and electrolyte imbalance due 
to diarrhea may have serious consequences, the agency is adding an 
additional direction in Sec.  335.50(d)(1): ``The labeling states 
`[bullet] drink plenty of clear fluids to help prevent dehydration 
caused by diarrhea.'''

IV. The Agency's Final Conclusions

    Based on the available evidence, the agency is issuing a final 
monograph establishing conditions under which OTC antidiarrheal drug 
products are generally recognized as safe and effective and not 
misbranded. Any drug product labeled, represented, or promoted for uses 
as an OTC antidiarrheal drug product that contains any of the 
ingredients listed in Sec.  310.545(a)(3)(i) or (a)(3)(ii) or that is 
not in conformance with the monograph (to be codified at 21 CFR part 
335) may be considered a new drug within the meaning of section 201(p) 
of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
321(p)) and misbranded under section 502 of the act (21 U.S.C. 352). 
Such a product cannot be marketed for antidiarrheal 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 accordance with Sec. Sec.  10.30 and 330.10(a)(12)(i). Any 
OTC antidiarrheal drug product initially introduced or initially 
delivered for introduction into interstate commerce after the 
compliance dates of the final rule for Sec.  310.545(a)(3)(i) or this 
final rule that is not in compliance with the regulations is subject to 
regulatory action.
    The agency is revoking the existing warning statement in Sec.  
369.20 for diarrhea preparations at the time that this monograph 
becomes effective. That warning is superseded by the requirements of 
the final monograph.
    Mandating warnings in an OTC drug monograph does not require a 
finding that any or all of the OTC drug products covered by the 
monograph actually caused an adverse event, and FDA does not so find. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
monographs and monograph rulemakings under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that warnings are necessary to ensure that 
these OTC drug products continue to be safe and effective for their 
labeled indications under ordinary conditions of use as those terms are 
defined in the act. This judgment balances the benefits of these drug 
products against their potential risks (see 21 CFR 330.10(a)).
    FDA's decision to act in this instance need not meet the standard 
of proof required to prevail in a private tort action (Glastetter v. 
Novartis Pharmaceuticals, Corp., 252 F.3d 986, 991 (8th Cir. 2001)). To 
mandate warnings, or take similar regulatory action, FDA need not show, 
nor do we allege, actual causation. For an expanded discussion of case 
law supporting FDA's authority to require such warnings, see Labeling 
of Diphenhydramine-Containing Drug Products for Over-the-Counter Human 
Use, a final rule that published in the Federal Register of December 6, 
2002 (67 FR 72555).

V. Analysis of Impacts

    An analysis of the costs and benefits of this regulation, conducted 
under Executive Order 12291, was discussed in the TFM for OTC 
antidiarrheal drug products (51 FR 16138 at 16147). (Executive Order 
12291 was revoked by Executive Order 12866.) The agency certified that 
under the Regulatory Flexibility Act the proposed rule would not have a 
significant economic impact on a substantial number of small entities. 
No comments were received on the economic impact of this rulemaking.
    FDA has examined the impacts of the final 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). 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 that has led to the 
development of this final rule was published on April 30, 1986, before 
the Unfunded Mandates Reform Act of 1995 was enacted. The agency 
explains in this final rule that the final rule will not 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.
    The agency concludes that this final rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
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 this 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 establish allowable monograph 
ingredients and labeling under which OTC antidiarrheal drug products 
are generally recognized as safe and effective. The agency has 
identified 45 manufacturers currently marketing 383 OTC antidiarrheal 
drug products containing bismuth subsalicylate (334), attapulgite (32), 
kaolin and pectin (13), polycarbophil (2), and calcium polycarbophil 
(2). This final rule will result in the reformulation or removal of 
about 50 products containing activated attapulgite, calcium 
polycarbophil, polycarbophil, and pectin. These products may be 
reformulated to contain bismuth subsalicylate or kaolin. The agency is 
unaware of any current marketing of bismuth subnitrate,

[[Page 18879]]

calcium hydroxide, charcoal (activated), potassium carbonate, or 
rhubarb fluidextract for antidiarrheal use.
    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. Some of the manufacturers of the 50 products 
containing nonmonograph active ingredients may elect not to reformulate 
(i.e., they may elect to discontinue marketing of the product). For 
those products that need reformulation, the cost can be significant. 
Because of the other monograph active ingredients available for 
reformulation, no manufacturer should need to change its dosage form; 
however, it 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 parts 210 and 211 (21 CFR parts 210 and 211).) The agency estimates 
the cost of reformulation to range form $100,000 to $500,000 per 
product. Therefore, if all 50 products are reformulated, the midpoint 
of the cost estimate implies total costs of $15 million. However, the 
agency believes the total costs will be much smaller because not all 
manufacturers will elect to reformulate and some may choose to 
discontinue a product line if sales are too low to justify the added 
cost and/or they also produce substitute products that do not require 
reformulation. Manufacturers may also elect to purchase reformulated 
products from another manufacturer and then be a distributor of that 
product.
    Because these products must be manufactured in compliance with the 
pharmaceutical current good manufacturing practices (parts 210 and 
211), all firms would have the necessary skills and personnel to 
perform these tasks either in-house or by contractual arrangement. The 
final rule does not require any new reporting or recordkeeping 
activities. No additional professional skills are needed.
    This final rule establishes the monograph for OTC antidiarrheal 
drug products and will require relabeling of all products covered by 
the monograph. Estimates of relabeling costs for the type of changes 
required by this rule vary greatly and range from $500 to $15,000 per 
stockkeeping unit (SKU) (individual products, packages, and sizes) 
depending on whether the products are nationally branded or private 
label. The agency assumes the same weighted average cost to relabel 
(i.e., $3,600 per SKU) that it estimated for the final rule requiring 
uniform label formats of OTC drug products (64 FR 13254 at 13279 to 
13281). Assuming 350 to 400 affected OTC SKUs in the marketplace, total 
one-time costs of relabeling would be $1.26 to 1.44 million. Because 
frequent labeling redesigns are a recognized cost of doing business in 
the OTC drug industry, these costs may be less. Manufacturers that make 
voluntary market-driven changes to their labeling during the 
implementation period can implement the regulatory requirements for a 
nominal cost.
    This final rule may have an economic impact on some small entities. 
The agency's drug listing system indicates that about 350 to 400 
products will need to be relabeled, and that this relabeling will be 
prepared by about 45 manufacturers, most of which are private label or 
contract manufacturers. Based on the Small Business Administration's 
determination that a small firm in this industry has fewer than 750 
employees, roughly 70 percent of the firms are considered small. The 
economic impact on any particular firm is very difficult to measure, 
because it will vary with the type and number of products affected, the 
number of SKUs per product, and the ability to coordinate these label 
changes with those required for other purposes. For example, assuming 
average industry costs, a small company that had 5 products with 3 SKUs 
each for a total of 15 SKUs would experience a one-time cost of 
$54,000. A small private label manufacturer with the same product line 
and 10 customers per SKU, for a total of 150 SKUs, would experience a 
one-time cost of $540,000. If one or more products needed to be 
reformulated, the costs would increase by $100,000 to $500,000 per 
formulation.
    Some of these relabeling costs will be mitigated because the agency 
is allowing 12 months for manufactures to implement the required 
labeling revisions for all products containing antidiarrheal active 
ingredients. Products with annual sales less than $25,000 have 12 
additional months. Therefore, many of the labeling revisions may be 
done in the normal course of business. Among the steps the agency is 
taking to minimize the impact on small entities are: (1) Providing 
enough time for implementation to enable entities to use up existing 
labeling stock, and (2) allowing the labeling changes required by this 
final monograph to be implemented concurrently with the labeling 
changes required by the new OTC drug labeling format final rule. The 
agency believes that these actions provide substantial flexibility and 
reductions in cost for small entities.
    The agency considered but rejected several labeling alternatives: 
(1) A shorter or longer implemention 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 coordination of the 
labeling changes resulting from implementation of the new OTC ``drug 
facts'' labeling and the antidiarrheal final rule may significantly 
reduce the costs of this final rule. A longer time period would 
unnecessarily delay the benefit of new labeling and revised 
formulations, where applicable, to consumers who self-medicate with 
these OTC antidiarrheal 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. However, a longer compliance date (24 
months) is being provided for products with annual sales less than 
$25,000.
    This analysis shows that the agency has undertaken important steps 
to reduce the burden to small entities. 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.

VI. 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 Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the 
labeling statements are 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

    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.

VIII. 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

[[Page 18880]]

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.

IX. Request for Comments

    This final monograph establishes labeling for OTC antidiarrheal 
drug products containing bismuth subsalicylate and kaolin. The warnings 
for products containing bismuth subsalicylate in Sec.  335.50(c)(2) 
include: (1) The Reye's syndrome warning in Sec.  201.314(h), (2) 
``Allergy alert: Contains salicylate. Do not take if you are [bullet] 
allergic to salicylates (including aspirin), [bullet] taking other 
salicylate products,'' (3) ``Do not use if you have [bullet] an ulcer 
[bullet] a bleeding problem,'' (4) ``Ask a doctor or pharmacist before 
use if you are taking any drug for [bullet] anticoagulation (thinning 
the blood) [bullet] diabetes [bullet] gout [bullet] arthritis,'' (5) 
``When using this product a temporary, but harmless, darkening of the 
stool and/or tongue may occur,'' and (6) ``Stop use and ask a doctor if 
[bullet] symptoms get worse [bullet] ringing in the ears or loss of 
hearing occurs [bullet] diarrhea lasts more than 2 days''.
    These warnings for products containing kaolin in Sec.  335.50(c)(3) 
include: (1) ``Ask a doctor or pharmacist before use if you are taking 
any other drugs. Try to use at least 3 hours before or after taking any 
other drugs,'' and (2) ``Stop use and ask a doctor if [bullet] symptoms 
get worse [bullet] diarrhea lasts more than 2 days''.
    In addition, products containing either ingredient must state: (1) 
``Do not use if you have [bullet] bloody or black stool,'' and (2) 
``Ask a doctor before use if you have [bullet] fever [bullet] mucus in 
the stool''. The agency notes that fever and use for more than 2 days 
were included in the ``Do not use'' warning proposed in Sec.  335.50(c) 
of the TFM (51 FR 16138 at 16149).
    The indications in this final rule are similar to those discussed 
in the TFM, and the directions in this final rule are based on the 
studies discussed in this document. While interested persons may 
comment on any portions of the labeling in this final rule, the agency 
would like to receive specific comments primarily on the warnings 
labeling in Sec.  335.50(c).
    This final rule also includes labeling requirements for products 
that meet the criteria established in Sec.  201.66(d)(10) (see Sec.  
335.50(e)). This reduced labeling results from the modified labeling 
format for OTC drug products in Sec.  201.66(d)(10), which did not 
exist when the TFM was published. Interested persons may also comment 
on this labeling.
    The agency is particularly interested in receiving comments on the 
specific labeling requirements discussed in this section of this 
document. Comments should be identified with the docket number found in 
brackets in the heading of 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. Received 
comments may be seen in the Dockets Management Branch between 9 a.m. 
and 4 p.m., Monday through Friday. If the comments justify a change in 
labeling, the agency will propose to amend the final monograph 
accordingly at a later date.

X. References

    The following references are on display in the Dockets Management 
Branch (see ADDRESSES) under Docket No. 78N-036D and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.

    1. Comment No. C85.
    2. Comment No. C92.
    3. Comment No. SUP12.
    4. Letter from W. E. Gilbertson, FDA, to A. R. Giaquinto, 
Schering-Plough Corp., coded LET20.
    5. Study IB-101, Comment No. CP2.
    6. Steffen Study, Protocol PB-103, Comments No. CP2 and SUP10.
    7. DuPont Study, Protocol PB-114, Comments No. CP2 and SUP10.
    8. Letter from W. E. Gilbertson, FDA, to P. Sinnott, The Procter 
and Gamble Co., coded LET26.
    9. Comment No. SUP8.
    10. Comment No. SUP13.
    11. Comment No. LET23.
    12. Comment No. LET24.
    13. Comment No. PR3.
    14. Comment No. SUP14.
    15. Comment No. TR1, pp. 43-46.
    16. Letter from W. E. Gilbertson, FDA, to P. Sinnott, The 
Procter and Gamble Co., coded LET27.
    17. Comment No. C94.
    18. Gryboski, J. D. et al., ``Bismuth Subsalicylate in the 
Treatment of Chronic Diarrhea in Childhood,'' American Journal of 
Gastroenterology, 80:871, 1985.
    19. Soriano-Brucker, H. et al., ``Bismuth Subsalicylate in the 
Treatment of Acute Diarrhea in Children: A Clinical Study,'' 
Pediatrics, 87:18-27, 1991.
    20. Figueroa, D. et al., ``Bismuth Subsalicylate Reduces Volume 
and Duration of Watery Diarrhea in Young Peruvian Children,'' 
Thirty-First Interscience Conference on Antimicrobial Agents and 
Chemotherapy, Chicago, IL, Prog. Abstr. 31:224 (Abstr. No. 754), 
1991.
    21. Letter from W. E. Gilbertson, FDA, to P. Sinnott, The 
Procter and Gamble Co., coded LET29.
    22. Comment No. PR8.
    23. Comment No. CP3.
    24. Comment No. SUP11.
    25. Comment No. PR4.
    26. Comment No. LET25.
    27. Comment No. C89.
    28. OTC Vol. 090005.
    29. Comment No. SUP09.
    30. Letter from W. E. Gilbertson, FDA, to G. H. Ishler, The 
Upjohn Co., coded LET2.
    31. Comment No. MM8.
    32. The United States Pharmacopeia Dispensing Information, 20th 
ed., Vol. I, United States Pharmacopeial Convention, Inc., 
Rockville, MD, pp. 1869-1870, 1999.
    33. OTC Vol. 090133.
    34. Comment No. SUP5.
    35. Comment No. AMD2.
    36. Comment No. SUP6.
    37. De Sola Pool, N. et al., ``A Comparison of Nonsystemic and 
Systemic Antidiarrheal Agents in the Treatment of Acute Nonspecific 
Diarrhea in Adults,'' Today's Therapeutic Trends, 52:31-38, 1987.
    38. DuPont, H. L. et al., ``A Randomized, Open-Label Comparison 
of Nonprescription Loperamide and Attapulgite in the Symptomatic 
Treatment of Acute Diarrhea,'' The American Journal of Medicine, 88 
supp. 6A:20-23, 1990.
    39. Food and Drug Administration, ``Guidelines for the Clinical 
Evaluation of Antidiarrheal Drugs,'' September 1977, in OTC Vol. 
09DFM.
    40. Letter from W. E. Gilbertson, FDA, to R. W. Soller, 
Nonprescription Drug Manufacturers Association, coded LET34.
    41. Letter from W. E. Gilbertson, FDA, to R. W. Soller, 
Nonprescription Drug Manufacturers Association, coded LET39.
    42. Rutledge, M. L. et al., ``Clinical Comparison of Calcium 
Polycarbophil and Kaolin-Pectin Suspensions in the Treatment of 
Acute Childhood Diarrhea,'' Current Therapeutic Research, 23:443-
447, 1978.
    43. Rutledge, M. L. et al., ``Calcium Polycarbophil in Acute 
Childhood Diarrhea,'' Clinical Pediatrics, 2:61-63, 1963.
    44. Grossman, A. J., R. C. Batterman, and P. Leifer, 
``Polyacrylic Resin: Effective Hydrophilic Colloid for the Treatment 
of Constipation,'' Journal of the American Geriatric Society, 5:187-
192, 1957.
    45. Roth, J. L. A., ``Effects of Polycarbophil as Enteral 
Hydrosorbent in Diarrhea,'' American Journal of Digestive Diseases, 
5:965-971, 1960.
    46. Pimparker, B. D. et al., ``Effect of Polycarbophil on 
Diarrhea and Constipation,'' Gastroenterology, 40:397-404, 1961.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

[[Page 18881]]

21 CFR Part 335

    Labeling, Over-the-counter drugs.

21 CFR Part 369

    Labeling, Medical devices, Over-the-counter drugs.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR 
chapter I is amended as follows:

PART 310--NEW DRUGS

0
1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.

0
2. Section 310.545 is amended by adding paragraph (a)(3)(i) heading, 
paragraphs (a)(3)(ii) and (d)(17), and by revising paragraph (d)(1) to 
read as follows:


Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (3) Antidiarrheal drug products--(i) Approved as of May 7, 1991.
* * * * *
    (ii) Approved as of April 19, 2004; April 18, 2005, for products 
with annual sales less than $25,000.
Attapulgite, activated
Bismuth subnitrate
Calcium hydroxide
Calcium polycarbophil
Charcoal (activated)
Pectin
Polycarbophil
Potassium carbonate
Rhubarb fluidextract
* * * * *
    (d) * * *
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3)(i), (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) 
(except as covered by paragraph (d)(3) of this section), (a)(8)(i), 
(a)(10)(i) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A), 
(a)(14) through (a)(15)(i), and (a)(16) through (a)(18)(i)(A) of this 
section.
* * * * *
    (17) April 19, 2004, for products subject to paragraph (a)(3)(ii) 
of this section. April 18, 2005, for products with annual sales less 
than $25,000.
* * * * *

0
3. Part 335 is added to read as follows:

PART 335--ANTIDIARRHEAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN 
USE

Subpart A--General Provisions
335.1 Scope.
335.3 Definitions.
Subpart B--Active Ingredients
335.10 Antidiarrheal active ingredients.
Subpart C--Labeling
335.50 Labeling of antidiarrheal drug products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

Subpart A--General Provisions


Sec.  335.1  Scope.

    (a) An over-the-counter antidiarrheal drug product in a form 
suitable for oral administration is generally recognized as safe and 
effective and is not misbranded if it meets each condition in this part 
and each general condition established in Sec.  330.1 of this chapter.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise 
noted.


Sec.  335.3  Definitions.

    As used in this part:
    (a) Antidiarrheal. A drug that can be shown by objective 
measurement to treat or control (stop) the symptoms of diarrhea.
    (b) Diarrhea. A condition characterized by increased frequency of 
loose, watery stools (three or more daily) during a limited period (24 
to 48 hours), usually with no identifiable cause.

Subpart B--Active Ingredients


Sec.  335.10  Antidiarrheal active ingredients.

    The active ingredient of the product consists of any one of the 
following when used within the dosage limits established for each 
ingredient in Sec.  335.50(d):
    (a) Bismuth subsalicylate.
    (b) Kaolin.

Subpart C--Labeling


Sec.  335.50  Labeling of antidiarrheal drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product either 
as an ``antidiarrheal'' or ``for diarrhea.''
    (b) Indications. The labeling of the product states, under the 
heading ``Use,'' one or more of the phrases listed in this paragraph 
(b), as appropriate. Other truthful and nonmisleading statements, 
describing only the indications for use that have been established and 
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 products containing bismuth subsalicylate identified in 
Sec.  335.10(a). The labeling states [select one of the following: 
``controls'' or ``relieves''] ``diarrhea''.
    (2) For products containing kaolin identified in Sec.  335.10(b). 
The labeling states ``helps firm stool within 24 to 48 hours''.
    (3) Additional indications--(i) When any additional indications are 
used, the heading ``Uses'' shall be used and each listed use shall be 
preceded by a bullet in accord with Sec.  201.66(b)(4) of this chapter.
    (ii) In addition to the indication in paragraph (b)(1) of this 
section, one or both of the following may be used for products 
containing bismuth subsalicylate in Sec.  335.10(a): ``[bullet] reduces 
number of bowel movements'' ``[bullet] helps firm stool''.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For products containing any ingredient identified in Sec.  
335.10. (i) ``Do not use if you have [bullet] bloody or black stool''.
    (ii) ``Ask a doctor before use if you have [bullet] fever [bullet] 
mucus in the stool''.
    (2) For products containing bismuth subsalicylate identified in 
Sec.  335.10(a). (i) The following shall appear in accordance with 
Sec.  201.66(c)(5)(ii) of this chapter.
    (A) The Reye's syndrome warning in Sec.  201.314(h) of this 
chapter.
    (B) ``Allergy alert: Contains salicylate. Do not take if you are 
[bullet] allergic to salicylates (including aspirin), [bullet] taking 
other salicylate products''.
    (ii) ``Do not use if you have [bullet] an ulcer [bullet] a bleeding 
problem''.
    (iii) ``Ask a doctor or pharmacist before use if you are taking any 
drug for [bullet] anticoagulation (thinning the blood) [bullet] 
diabetes [bullet] gout [bullet] arthritis''.
    (iv) ``When using this product a temporary, but harmless, darkening 
of the stool and/or tongue may occur''.
    (v) ``Stop use and ask a doctor if [bullet] symptoms get worse 
[bullet] ringing in the ears or loss of hearing

[[Page 18882]]

occurs [bullet] diarrhea lasts more than 2 days''.
    (3) For products containing kaolin identified in Sec.  335.10(b). 
(i) ``Ask a doctor or pharmacist before use if you are taking any other 
drugs. Try to use at least 3 hours before or after taking any other 
drugs.''
    (ii) ``Stop use and ask a doctor if [bullet] symptoms get worse 
[bullet] diarrhea lasts more than 2 days''.
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing any ingredient identified in Sec.  
335.10. The labeling states ``[bullet] drink plenty of clear fluids to 
help prevent dehydration caused by diarrhea''.
    (2) For products containing bismuth subsalicylate identified in 
Sec.  335.10(a). The labeling states ``[bullet] adults and children 12 
years and over:'' 525 milligrams ``every 1/2 to 1 hour, or'' 1,050 
milligrams ``every hour as needed [bullet] do not exceed'' 4,200 
milligrams ``in 24 hours [bullet] use until diarrhea stops but not more 
than 2 days [bullet] children under 12 years: ask a doctor''.
    (3) For products containing kaolin identified in Sec.  335.10(b). 
The labeling states ``[bullet] adults and children 12 years and over:'' 
26.2 grams ``after each loose stool [bullet] continue to take every 6 
hours until stool is firm but not more than 2 days [bullet] do not 
exceed'' [262 grams] ``in 24 hours [bullet] children under 12 years of 
age: ask a doctor''.
    (e) Products that meet the criteria established in Sec.  
201.66(d)(10) of this chapter. The information described in Sec.  
201.66(c) of this chapter shall be printed in accordance with the 
following specifications.
    (1) The labeling shall meet the requirements of Sec.  201.66(c) of 
this chapter except that the information in Sec.  201.66(c)(3) of this 
chapter may be omitted, and the information in Sec.  201.66(c)(5) and 
(c)(6) of this chapter may be presented as follows:
    (i) The words ``Contains salicylate.'' may be omitted from the 
warning in Sec.  335.50(c)(2)(i)(B).
    (ii) The subheading ``When using this product'' in Sec.  
335.50(c)(2)(iv) may be omitted.
    (iii) The words ``continue to'' may be omitted from the directions 
in Sec.  335.50(d)(3).
    (2) The labeling shall be printed in accordance with the 
requirements of Sec.  201.66(d) of this chapter except that any 
requirements related to Sec.  201.66(c)(3) of this chapter and the 
bullet in the warning in Sec.  335.50(c)(1)(i) may be omitted.

PART 369--INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND 
DEVICES FOR OVER-THE-COUNTER SALE

0
4. The authority citation for 21 CFR part 369 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371.


Sec.  369.20  [Amended]

    5. Section 369.20 Drugs; recommended warning and caution statements 
is amended by removing the entry for ``DIARRHEA PREPARATIONS.''

    Dated: March 31, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-9380 Filed 4-16-03; 8:45 am]
BILLING CODE 4160-01-S