[Federal Register: August 5, 2003 (Volume 68, Number 150)]
[Proposed Rules]               
[Page 46133-46138]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05au03-20]                         

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 334

[Docket No. 1978N-036L]
RIN 0910-AA01

 
Laxative Drug Products for Over-the-Counter Human Use; Proposed 
Amendment to the Tentative Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

SUMMARY: The Food and Drug Administration (FDA) is reopening the 
administrative record and proposing to amend the tentative final 
monograph (proposed rule) for over-the-counter (OTC) laxative drug 
products to reclassify the bulk-forming laxative psyllium ingredients 
(psyllium (hemicellulose), psyllium hydrophilic mucilloid, psyllium 
seed, psyllium seed (blond)), psyllium seed husks, plantago ovata 
husks, and plantago seed)) in a granular dosage form from Category I 
(generally recognized as safe and effective and not misbranded) to 
Category II (not generally recognized as safe and effective or 
misbranded). The granular dosage form affected by this proposal 
includes, but is not limited to, any granules that are swallowed dry 
prior to drinking liquid; any granules that are dispersed, suspended, 
or partially dissolved in liquid prior to swallowing; any granules that 
are chewed, partially chewed, or unchewed, and then washed down (or 
swallowed) with liquid; and any granules that are sprinkled over food. 
FDA is issuing this proposed rulemaking after considering data and 
information on the safety of some currently marketed products 
containing psyllium in a granular dosage form. This proposed rulemaking 
does not apply to nongranular dosage forms of psyllium, such as 
powders. FDA has determined that psyllium in a granular dosage form 
presents an unacceptable safety risk to consumers because esophageal 
obstruction continues to occur despite currently required label 
warnings and directions. This proposal is part of FDA's ongoing review 
of OTC drug products.

DATES: Submit written or electronic comments by November 3, 2003; 
submit written or electronic comments on the FDA's economic impact 
determination by November 3, 2003. See section IX for the effective 
date of any final rule that may publish based on this proposal.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (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: Arlene Solbeck, 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 advance notice of proposed rulemaking (ANPRM) for OTC 
laxative, antidiarrheal, emetic, and antiemetic drug products (40 FR 
12902 at 12906, March 21, 1975), the advisory review panel on OTC 
laxative, antidiarrheal, emetic, and antiemetic drug products (the 
Panel) recommended Category I status for the OTC bulk laxative psyllium 
ingredients, which include plantago seed, plantago ovata husks, 
psyllium (hemicellulose), psyllium hydrophilic mucilloid, psyllium 
seed, psyllium seed (blond), and psyllium seed husks. FDA concurred 
with the Panel's Category I classification of these ingredients in the 
tentative final monograph (TFM) published in the Federal Register of 
January 15, 1985 (50 FR 2124 at 2152).
    In the ANPRM, the Panel recommended a warning statement (Sec.  
334.52(a)(1) 21 CFR 334.52(a)(1)) for bulk forming laxatives that 
advised drinking a full glass, 8 ounces (oz), of liquid with each dose 
and direction statements (Sec.  334.10(f)) advising adequate fluid 
intake. The Panel concluded that adequate fluid intake was necessary 
for the proper use of bulk-forming laxatives because esophageal and 
intestinal obstruction had occurred from ingesting bulk-forming 
laxatives with insufficient water or in the presence of certain disease 
conditions (40 FR 12902 at 12908). FDA discussed the risk of esophageal 
obstruction from certain bulk laxative ingredients, including water-
soluble gums, and the need for adequate fluid intake (8 oz) with each 
dose in comments 36 and 37 of the TFM (50 FR 2124 at 2131 and 2132). 
FDA

[[Page 46134]]

proposed the direction ``Drink a full glass (8 oz) of liquid with each 
dose'' to define adequate fluid intake.
    In the Federal Register of October 1, 1986 (51 FR 35136), FDA 
amended the TFM and proposed that bulk laxative ingredients be 
administered in divided doses rather than a single daily dose. The 
amendment was based on data that indicated the maximum daily dose of 
some bulk laxatives was so large that it may pose a risk of esophageal 
obstruction if taken at one time (51 FR 35136).
    After receiving reports of cases of esophageal obstruction due to 
ingestion of laxative products containing water-soluble gums, 
hydrophilic gums, and hydrophilic mucilloids, including psyllium, FDA 
published a proposed rule in the Federal Register of October 30, 1990 
(55 FR 45782), to require a warning in the labeling of all OTC drug 
products containing water-soluble gums as active ingredients. FDA added 
the warning to alert users to take adequate fluid and to avoid using 
these products if the person had previously experienced any difficulty 
in swallowing. FDA published a final rule requiring new warning and 
direction statements in the Federal Register of August 26, 1993 (58 FR 
45194) and amended that rule in the Federal Register of March 17, 1999 
(64 FR 13254 at 13292). The current warnings and directions (in Sec.  
201.319(b) (21 CFR 201.319(b)) state:
    ```Choking' [highlighted in bold type]: Taking this product 
without adequate fluid may cause it to swell and block your throat 
or esophagus and may cause choking. Do not take this product if you 
have difficulty in swallowing. If you experience chest pain, 
vomiting, or difficulty in swallowing or breathing after taking this 
product, seek immediate medical attention;'' and
    ```Directions' [highlighted in bold type]:'' (Select one of the 
following, as appropriate: ``Take'' or ``Mix'') ``this product 
(child or adult dose) with at least 8 ounces (a full glass) of water 
or other fluid. Taking this product without enough liquid may cause 
choking. See choking warning.''

II. Adverse Events Regarding Psyllium Ingredients in a Granular Dosage 
Form

    A granular dosage form of psyllium, as a single ingredient product 
or a combination product containing psyllium (82 percent) and senna (18 
percent), was introduced into the OTC market around 1979. In 1989, a 
major manufacturer of psyllium granular dosage form products reported 
to FDA 61 cases of esophageal obstruction and choking that occurred 
between February 1980 and December 1988 (Ref. 1). No deaths occurred, 
but these reports indicated that 19 people were hospitalized and 31 
people required medical intervention in the form of endoscopy to 
dislodge the esophageal obstructions. The same manufacturer had 
submitted a comment in 1985 (Ref. 2) to the laxative TFM stating that 
consumer labeling of psyllium containing laxatives should: (1) State 
that bulk-forming laxatives have the potential to block the esophagus, 
particularly in the presence of esophageal narrowing or when consumed 
with insufficient liquid, (2) bear a warning to drink sufficient 
amounts of fluid, (3) advise people with esophageal narrowing against 
using the product, and (4) direct individuals who experience esophageal 
obstruction, regurgitation, and difficulty swallowing to seek immediate 
medical attention. In response to the comment (Ref. 3), FDA suggested 
that the cases of esophageal blockage may be related to the 
manufacturer's directions for use, which instruct consumers to place 
the granules in the mouth and swallow, without chewing, prior to 
drinking liquid. FDA noted that other psyllium-containing OTC laxative 
drug products are mixed into liquid or food or, in the case of wafers 
and chewable tablets, chewed before swallowing. FDA indicated that it 
did not consider the manufacturer's directions for its products 
adequate to provide for their ``safe OTC use'' and suggested that, to 
retain OTC status, the manufacturer should consider reformulating the 
products to be suspended in ``no less than 8 ounces of liquid per dose 
prior to consumption'' or provide more specific labeling information 
indicating that the product is ``not to be taken directly by spoon or 
swallowed dry.'' FDA stated that the manufacturer's products might 
require a new drug application (NDA) for use under medical supervision. 
FDA mentioned other reports of esophageal obstruction and asphyxiation 
associated with the ingestion of water-soluble gums, hydrophilic gums, 
and hydrophilic mucilloids, including psyllium.
    In response to FDA's concerns (Ref. 4), the manufacturer noted that 
it took the following actions to resolve the problems of esophageal 
obstruction and choking: (1) In 1985, the directions for use were 
modified to emphasize the need to have adequate fluid intake, (2) a 
patient package insert was placed inside each package stressing the 
importance of taking sufficient liquid, and (3) a ``dear doctor'' 
letter was issued in February 1985 to U.S. physicians calling attention 
to the need for adequate fluid intake to avoid the risk of esophageal 
obstruction. The manufacturer stated that only 15 of the 61 cases 
occurred after it took these actions.
    As noted previously, on August 26, 1993, FDA published a final rule 
in the Federal Register requiring warning and direction statements in 
the labeling of all OTC drug products containing water-soluble gums as 
active ingredients, including psyllium. Additional warnings and 
directions were added to alert users to consume adequate fluid and to 
avoid using such products if the person had previously experienced any 
difficulty in swallowing.
    Despite the new required warnings and directions and other labeling 
changes initiated by the manufacturer, FDA continued to receive reports 
of choking and esophageal obstruction associated with psyllium, 
particularly the granular dosage form. In November 2000, FDA reviewed 
reports (postmarketing safety review) from its adverse event reporting 
system (AERS) database and the medical literature for the time between 
1966 and 2000 (Ref. 5). FDA identified 98 reported cases of esophageal 
obstruction and choking associated with the use of psyllium products 
(Ref. 6). Four deaths occurred and 66 cases required medical 
intervention and/or hospitalization. Of these 98 cases, 78 (80 
percent), including 1 death and 59 cases that required medical 
intervention and/or hospitalization, were related to the granular 
dosage form that is swallowed unchewed while drinking liquid. Medical 
intervention included endoscopy (in 41 cases), esophageal dilatation, 
surgery, nasogastric tube, Heimlich maneuver, and polypectomy snare. 
The mean age in these cases (27 cases not reporting age) was 69 years. 
Possible risk factors were identified in 52 percent of the cases, 
although there were 37 cases with no reported or apparent risk factors.
    FDA also identified 13 (11 percent) cases of choking-related events 
(and two cases of esophageal obstruction (2 percent)) related to a 
powder or wafer psyllium product. The label of these products stated 
that the powder should be mixed with 8 oz of liquid and the wafers 
should be consumed with 8 oz of liquid. The mean age in these cases was 
71 years. There were three deaths (two from asphyxiation and one from 
bronchus obstruction) and seven people who required hospitalization. 
Three cases (4 percent) of choking and/or difficulty swallowing and 
four cases (5 percent) of esophageal obstruction were related to the 
use of another psyllium product available as a powder or toasted 
granules. The product directions indicated to mix the powder with 
liquid

[[Page 46135]]

and sprinkle the granules on food. All seven cases (mean age was 64 
years) required hospitalization.
    Although these reports indicate there were fewer deaths related to 
the granular dosage form that was swallowed unchewed while drinking 
liquid (one out of four), there were significantly more overall cases 
of esophageal obstruction (78 out of 98) and cases that required 
medical intervention (59 out of 66) with this dosage form.
    In January 2001, FDA requested and obtained updated adverse event 
reports from a current major manufacturer of psyllium laxative products 
in granular dosage form for the time period between January 1999 and 
January 2001 (Ref. 7). In April 2002, FDA received an update from this 
manufacturer for the time period after January 2001 (Ref. 8). This 
manufacturer's product labeling contained the following directions:
    (1) Moisten your mouth with a drink of water or any cool 
beverage, (2) Place a teaspoonful of granules on your tongue. If you 
prefer, take only a partial teaspoonful at a time, (3) Without 
chewing, wash granules down with water or any cool beverage, (4) 
Repeat steps 1-3 until the recommended dose has been swallowed. Be 
sure to drink at least 8 ounces of cool liquid.
    FDA's reviews (Refs. 9 and 10) of these reports identified 44 
additional cases of adverse events related to esophageal obstruction 
between January 1999 and May 2002. No deaths were reported, but 13 of 
the reported cases were considered serious events requiring medical 
intervention (11 underwent endoscopy). The adverse event reports 
suggested that most of the people using the products followed the 
directions on the label (information on the dose taken was available in 
36 out of 44 cases). Most people (27 out of 35) took sufficient fluid 
with the product, while insufficient fluid intake may have contributed 
to the esophageal obstruction in 7 cases.
    In summary, FDA has received 142 cases of adverse events regarding 
esophageal obstruction and choking associated with psyllium between 
1966 and May 2002. Of these 142 cases, 59 occurred after publication of 
the 1993 required warning (58 FR 45194) with 45 reported to have 
occurred during the last 3 years alone. Eleven of these 45 reported 
cases (25 percent) involved hospitalization and/or the need for 
invasive procedures.
    Based on the data reviewed, and despite the warnings it has 
mandated, FDA now believes that there still exists a significant safety 
problem with esophageal obstruction associated with psyllium laxative 
products in granular dosage form, particularly products that are 
swallowed dry, swallowed partially moistened prior to drinking liquid, 
and swallowed unchewed while drinking liquid. FDA is concerned that a 
consumer ingesting this granular dosage form is less likely to drink 
adequate amounts of fluid with the product than a consumer instructed 
to mix the product in 8 oz of fluid prior to ingestion. Multiple 
labeling changes, including additional warnings and enhanced directions 
to take adequate fluid, have not alleviated this problem. Rather, the 
problem seems to have worsened. During the first 10 years of marketing, 
61 cases of esophageal obstruction were reported compared to 44 cases 
during the last 3 years alone. In addition, FDA is concerned that the 
incidence of serious adverse events for these products is underreported 
because reporting for products marketed under an OTC drug monograph is 
not currently mandatory.

III. FDA's Tentative Conclusion on OTC Psyllium Ingredients in a 
Granular Dosage Form

    FDA now considers OTC laxative drug products containing psyllium 
ingredients in granular dosage form as presenting an unacceptable 
health risk to consumers. These drug products include, but are not 
limited to: (1) Any granules that are swallowed dry prior to drinking 
liquid, (2) any granules that are dispersed, suspended, or partially 
dissolved in liquid prior to swallowing, (3) any granules that are 
chewed, partially chewed, or unchewed, and then washed down (or 
swallowed) with liquid, and (4) any granules that are sprinkled over 
food.
    FDA continues to receive reports of esophageal obstruction and 
choking associated with these products despite the warning and 
direction statements required for all water soluble gums in Sec.  
201.319. Therefore, due to the significant safety risk these products 
pose, FDA is proposing to reclassify bulk laxative psyllium ingredients 
in granular dosage form from Category I (monograph) to Category II 
(nonmonograph). FDA proposes to add these ingredients in granular 
dosage form to the list of bulk laxatives in Sec.  310.545(a)(12)(i) 
(21 CFR 310.545(a)(12)(i)) and to amend proposed Sec.  334.10 (bulk-
forming laxative active ingredients) to exclude the granular dosage 
form.
    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 find so. 
Nor does FDA's requirement of warnings repudiate the prior OTC drug 
regulations 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 
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 Federal Food, Drug, and Cosmetic Act (the act). This judgment 
balances the benefits of these drug products against their potential 
risks (see Sec.  330.10(a) 21 CFR 330.10(a)). In the current situation, 
FDA has determined that warnings are not adequate to address the 
significant safety risks that these products pose.
    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, final rule'' (67 FR 72555, December 6, 2002).
    Accordingly, if a final rule based on this proposal issues any drug 
product containing any psyllium ingredients in granular dosage form 
will be considered nonmonograph and misbranded under section 502 of the 
act (21 U.S.C. 352). This type of drug product would also be considered 
a new drug under section 201(p) of the act (21 U.S.C. 321(p)) for which 
an approved application under section 505 of the act (21 U.S.C. 355), 
and set forth in part 314 of the regulations, is required for 
marketing. If a final rule is based on this proposal issues, it would 
apply to any OTC drug product containing psyllium ingredients in 
granular dosage form that is initially introduced or initially 
delivered for introduction into interstate commerce after the effective 
date of the final rule. Further, any OTC drug product that was 
previously initially introduced or initially delivered for introduction 
into interstate commerce could not then be repackaged or relabeled 
after the effective date of the final rule.

IV. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-12), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and

[[Page 46136]]

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).
    FDA believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
The proposed rule is not a significant regulatory action as defined by 
the Executive order and so is not subject to review under the Executive 
order. The Unfunded Mandates Reform Act of 1995 does not require FDA to 
prepare a statement of costs and benefits for this proposed rule, 
because the proposed rule is not expected to result in any 1-year 
expenditures that would exceed $100 million adjusted for inflation. The 
current inflation adjusted statutory threshold is about $110 million.
    The purpose of this proposed rule is to establish conditions under 
which OTC bulk-forming laxative psyllium ingredients in a granular 
dosage form are not generally recognized as safe and effective. FDA's 
drug listing system (DLS) identifies nine currently marketed OTC 
laxative drug products containing psyllium ingredients in granular 
dosage form and FDA is aware of at least one other product not in its 
DLS. One manufacturer currently markets three stock keeping units 
(SKUs) (individual products, packages, and sizes) of the granular 
dosage form that requires the product to be swallowed dry while 
drinking liquid; two manufacturers market two SKUs each, and one 
manufacturer markets one SKU. It is likely that there may be a few 
additional products that are currently not included in FDA's DLS. This 
proposed rule, when finalized, will result in the reformulation or 
removal of probably less than a dozen products.
    [sbull] Reformulation Costs
    Some manufacturers 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. The cost to 
reformulate a product will vary greatly depending on the nature of the 
change in the formulation, the product, the process, and the size of 
the firm. A manufacturer may elect to change the dosage form of the 
psyllium product or to substitute other monograph ingredients. This 
would require the manufacturer to redo the validation (product, 
process, new supplier), conduct stability tests, change master 
production records in order to insure compliance with good 
manufacturing practice, and, for some dosage forms, conduct 
palatability tests. (See section 501(a)(1)(B) of the act (21 U.S.C. 
351(a)(1)(B) and 21 CFR parts 210 and 211.) FDA estimates the cost of 
reformulation to range from $100,000 to $500,000 per product. 
Therefore, if 10 products are reformulated, the midpoint of the cost 
estimate implies total costs of $3,000,000. However, FDA 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. 
Competitive market forces and increased public awareness of a potential 
safety hazard of these ingredients in a granular dosage form would most 
likely lead all manufacturers to move to alternative products over 
time.
    [sbull] Relabeling Costs
    Manufacturers of these products will also incur costs to relabel 
their products to reflect the new formulation. Estimates of relabeling 
costs vary greatly and range from $3,000 to $5,000 per SKU depending on 
whether the products are nationally branded or private label. FDA 
estimates that manufacturers with more than one affected SKU will 
likely discontinue one or more SKUs. If some SKUs are discontinued, FDA 
estimates that only three to six SKUs will need to be relabeled as a 
result of reformulation. If these SKUs are relabeled, the total one-
time cost of relabeling could range from $9,000 (three SKUs x $3,000) 
to $30,000 (six SKUs x $5,000). This relabeling cost should not be a 
significant economic impact on a substantial number or small entities.
    Some manufacturers may choose to submit an NDA deviation for their 
psyllium product in accordance with Sec.  330.11. Overall, there may be 
fewer costs incurred by this process than by submission of a full NDA.
    Because these products must be manufactured in compliance with the 
pharmaceutical current good manufacturing practices (21 CFR parts 210 
and 211), all firms have the necessary skills and personnel to perform 
the tasks of reformulation, validation, and relabeling either in-house 
or by contractual arrangement. The rule will not require any new 
reporting and recordkeeping activities. No additional professional 
skills are needed.
    [sbull] Regulatory Alternatives Considered
    FDA considered but rejected the following additional alternatives: 
(1) Leave these products in the monograph, and (2) an exemption from 
coverage for small entities. FDA does not consider either of these 
approaches acceptable because they do not assure that consumers will 
have safe OTC psyllium laxative drug products in a granular dosage 
form. FDA does not believe that there are any significant alternatives 
to the proposed rule that would adequately provide for the safe use of 
these OTC drug products.
    FDA does not believe that this proposed rule would have a 
significant economic impact on a substantial number of small entities. 
However, FDA recognizes the uncertainty of its estimates with respect 
to the number of affected small entities and products, as well as the 
economic impact of the rule on those small entities. Thus, this 
economic analysis, together with other relevant sections, serves as 
FDA's initial regulatory flexibility analysis.
    Finally, FDA specifically invites public comment regarding any 
substantial or significant economic impact that this proposed rule 
would have on OTC laxative drug products containing psyllium 
ingredients in a granular dosage form. Types of impact may include, but 
are not limited to, the costs associated with reformulation, 
relabeling, or repackaging. Comments regarding the impact of this 
rulemaking on OTC laxative drug products containing these ingredients 
should be accompanied by appropriate documentation. FDA is providing a 
period of 90 days from the date of publication of this proposed rule in 
the Federal Register for comments on this subject to be developed and 
submitted. FDA will evaluate any comments and supporting data that are 
received and will reassess the economic impact of this rulemaking in 
the preamble to the final rule.

[[Page 46137]]

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that any relabeling resulting from this 
proposed rule is not subject to review by the Office of Management and 
Budget because it does not constitute a ``collection of information'' 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). 
Rather, the relabeling statements are in the TFM for OTC laxative drug 
products (50 FR 2124 and 51 FR 35136) and 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)).

VI. Environmental Impact

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

VII. Federalism

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

VIII. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document and may be accompanied by a supporting 
memorandum or brief. Received comments may be seen in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

IX. Proposed Effective Date

    FDA is proposing that any final rule that may issue based on this 
proposal become effective 180 days after its date of publication in the 
Federal Register.

X. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) under Docket No. 78N-036L, unless otherwise 
noted, and may be seen by interested persons between 9 a.m. and 4 p.m., 
Monday through Friday.
    1. Adverse Drug Reaction Reports, Ref. 7 in OTC vol. AF, Docket 
No. 90N-0200, Division of Dockets Management.
    2. Comment No. C00100.
    3. Comment No. LET45.
    4. Comment No. LET46.
    5. Adverse Event Reports from 1966 to 2000 for Psyllium Laxative 
Products (Perdiem, Metamucil, and Serutan) collected by FDA's Office 
of Compliance, in OTC vol. 090TFM6.
    6. FDA, Office of Postmarketing Drug Risk Assessment (OPDRA) 
(Project ID (PID) 000607) regarding Psyllium Laxative Products 
Associated with Esophageal Obstruction and Choking, November 17, 
2000, in OTC vol. 090TFM6.
    7. Adverse Event Reports from January 1999 to January 2001 for 
Overnight Relief PERDIEM and Fiber Therapy PERDIEM collected by 
FDA's Office of Compliance in January 2001, in OTC vol. 090TFM6.
    8. Adverse Event Reports from October 2000 to January 2002 for 
Overnight Relief PERDIEM and Fiber Therapy PERDIEM collected by 
FDA's Office of Compliance in April 2002, in OTC vol. 090TFM6.
    9. FDA, Cases of Esophageal Obstruction Associated with PERDIEM 
(January 1999 to January 2001), in OTC vol. 090TFM6.
    10. FDA, OPDRA Postmarketing Safety Review (PID D020201) 
regarding Senokot and Psyllium Laxative Products Associated with 
Esophageal Obstruction and Choking, May 15, 2002, in OTC vol. 
090TFM6.

List of Subjects

21 CFR Part 310

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

21 CFR Part 334

    Labeling, Over-the-counter drugs.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR parts 310 and 334 (as proposed in the Federal 
Register of January 15, 1985 (50 FR 2124), October 1, 1986 (51 FR 
35136), September 2, 1993 (58 FR 46589), March 31, 1994 (59 FR 15139), 
September 2, 1997 (62 FR 46223), May 21, 1998 (63 FR 27886), and June 
19, 1998 (63 FR 33592)), be amended as follows:

PART 310--NEW DRUGS

    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.
    2. Section 310.545 is amended by redesignating paragraph (a)(12)(i) 
as paragraph (a)(12)(i)(A), by adding new paragraph (a)(12)(i)(B), by 
revising paragraph (d) introductory text and paragraph (d)(1), and by 
adding new paragraph (d)(38) to read as follows:


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

    (a) * * *
    (12) * * *
    (i)(B) Bulk laxatives--Approved as of [date of publication of final 
rule in the Federal Register].
    Psyllium (hemicellulose), psyllium hydrophilic mucilloid, psyllium 
seed, psyllium seed (blond), psyllium seed husks, plantago husks, 
plantago seed, in a granular dosage form including, but not limited to 
any granules that are:
    (1) Swallowed dry prior to drinking liquid,
    (2) Dispersed, suspended, or partially dissolved in liquid prior to 
swallowing,
    (3) Chewed, partially chewed, or unchewed, and then washed down (or 
swallowed) with liquid, or
    (4) Sprinkled over food.
* * * * *
    (d) Any OTC drug product that is not in compliance with this 
section is subject to regulatory action if initially introduced or 
initially delivered for introduction into interstate commerce after the 
dates specified in paragraphs (d)(1) through (d)(38) of this section.
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) 
(except as covered by paragraph (d)(3) of this section), paragraphs 
(a)(8)(i), (a)(10)(i) through (a)(10)(iii), (a)(12)(i)(A), (a)(12)(ii) 
through (a)(12)(iv)(A), (a)(14) through (a)(15)(i), (a)(16) through 
(a)(18)(i)(A), (a)(18)(ii) (except as covered by paragraph (d)(22) of 
this section), paragraphs (a)(18)(iii), (a)(18)(iv), (a)(18)(v)(A), and 
(a)(18)(vi)(A) of this section.
* * * * *
    (38) [Date 180 days after date of publication of final rule in the 
Federal Register], for products subject to paragraph (a)(12)(i)(B) of 
this section.

[[Page 46138]]

PART 334--LAXATIVE DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    3. The authority citation for 21 CFR part 334 continues to read as 
follows:

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


Sec.  334.10  [Amended]

    4. Section 334.10 Bulk-forming laxative active ingredients as 
proposed on January 15, 1985 (50 FR 2124), is proposed to be amended by 
revising paragraph (f) to read as follows:
* * * * *
    (f) Psyllium ingredients, except those listed in Sec.  
310.545(a)(12)(i)(B) of this chapter.

    Dated: July 25, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-19808 Filed 8-4-03; 8:45 am]

BILLING CODE 4160-01-S