[Federal Register Volume 72, Number 60 (Thursday, March 29, 2007)]
[Rules and Regulations]
[Pages 14669-14674]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-5740]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 310

[Docket No. 1978N-0036L] (formerly Docket No. 1978N-036L)
RIN 0910-AF38


Laxative Drug Products for Over-the-Counter Human Use; Psyllium 
Ingredients in Granular Dosage Forms

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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

SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
establishing that over-the-counter (OTC) laxative drug products in 
granular dosage form containing the bulk-forming psyllium ingredients 
(psyllium (hemicellulose), psyllium hydrophilic mucilloid, psyllium 
seed, psyllium seed (blond), psyllium seed husks, plantago ovata husks, 
and plantago seed) are not generally recognized as safe and effective 
(GRASE) and are misbranded. This final rule includes, but is not 
limited to, any granules that are swallowed dry prior to drinking 
liquid; dispersed, suspended, or partially dissolved in liquid prior to 
swallowing; chewed, partially chewed, or unchewed, and then washed down 
(or swallowed) with liquid; or sprinkled over food. FDA is issuing this 
final rule after considering reports of esophageal obstruction 
associated with the use of psyllium laxatives in granular dosage form. 
These cases continue to occur despite efforts to promote safe use 
through label warnings and directions. This final rule does not apply 
to psyllium laxatives in nongranular dosage forms, such as powders, 
tablets, or wafers. This final rule is part of FDA's ongoing review of 
OTC drug products.

DATES: Effective Date: This rule is effective October 1, 2007.
    Compliance Date: The compliance date for all products subject to 
this final rule, including products with annual sales less than 
$25,000, is October 1, 2007.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number, found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts, and/or go to 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Reynold Tan, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, MS 5411, Silver Spring, MD 20993-0002, 301-
796-2090.

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 (GRASE and not misbranded) status for the 
OTC bulk laxative psyllium ingredients, which included 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 (21 CFR 
334.52(a)(1)) for bulk-forming laxatives that advised drinking a full 
glass, 8 ounces (oz), of liquid with each

[[Page 14670]]

dose and direction statements (Sec.  334.10(f)) advising adequate fluid 
intake (40 FR 12902 at 12942). 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 12908). FDA discussed in 
comments 36 and 37 of the TFM (50 FR 2124 at 2131 and 2132) 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. FDA 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 daily doses of bulk-forming laxative 
ingredients be administered in divided doses, rather than a single 
dose. The amendment was based on data that indicated the maximum daily 
dose of some bulk-forming laxatives was so large that it could pose a 
risk of esophageal obstruction if taken at one time (51 FR 35136).
    Subsequently, cases of esophageal obstruction due to ingestion of 
laxative products containing water-soluble gums, hydrophilic gums, and 
hydrophilic mucilloids, including psyllium, were reported and 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 followed up by publishing 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.''
    FDA later considered data and other information about the safety of 
laxative products in granular dosage form containing psyllium, one of 
the active ingredients included in the water-soluble gum category. FDA 
tentatively concluded that these products posed an unacceptable safety 
risk, because esophageal obstructions continued to occur with these 
products despite requiring label warnings and directions. In the 
Federal Register of August 5, 2003 (68 FR 46133), FDA proposed an 
amendment to the laxative TFM to reclassify psyllium laxatives in 
granular dosage form from Category I to Category II (not GRASE or 
misbranded). In response to the proposed amendment, one manufacturer of 
a psyllium laxative product in a granular dosage form submitted a 
comment that is discussed in section II of this document.

II. FDA's Conclusions on the Comment

    (Comment 1) The comment disagreed with FDA's proposal to reclassify 
psyllium laxative products in granular dosage form from Category I to 
Category II. The comment argued that the proposed rule should be 
withdrawn for the following reasons:
    <bullet> FDA's analysis overstated the risks of granular psyllium.

The comment stated that the number of events potentially related to 
psyllium products in granular dosage form is small relative to the 
number of doses taken by consumers. Further, of the 78 total cases of 
esophageal obstruction recorded for the company's granular dosage form 
product in FDA's Adverse Event Reporting System by the year 2000 (Ref. 
1), only 17 cases had occurred since 1989. The comment's product was 
introduced to the U.S. market in 1980. Therefore, the comment contended 
that the 17 cases that occurred from 1989 to 2000 was not a basis for 
increased safety concern considering that 61 cases occurred from 1980 
to 1989.
    <bullet> FDA's analysis concentrated improperly on the granular 
dosage form of psyllium products.

The comment argued that the data reviewed by FDA contained information 
suggesting that psyllium products in powder dosage forms may present 
more serious safety problems (e.g., asphyxiation) than granular dosage 
forms. The comment further contended that because FDA published the 
August 26, 1993, final rule requiring warning and direction statements 
for all water-soluble gum products, FDA has focused solely on psyllium 
products in granular dosage form and ignored serious adverse effects 
associated with other dosage forms. The comment argued that the failure 
to use the same methods to obtain adverse events data for psyllium 
products in both granular and nongranular dosage forms undermines FDA's 
conclusion that only granular dosage forms pose an unacceptable risk. 
Of the 98 adverse events associated with all psyllium products recorded 
by FDA between 1966 to 2000 (Ref. 1), 3 deaths were associated with 
powder dosage forms compared to only 1 death associated with granular 
dosage forms, which the comment contended was not directly caused by 
the granular dosage form (Ref. 2). The comment stated that FDA 
emphasized the single fatality associated with psyllium laxatives in 
the granular dosage form, but ignored the fatalities associated with 
psyllium laxatives in nongranular dosage forms. The comment stated that 
the record of fatalities did not support FDA's conclusions concerning 
the risk from granular dosage forms containing psyllium. Rather, FDA 
should have requested safety records from manufacturers of nongranular 
dosage forms, similar to those requested from the distributor of a 
granular product.
    <bullet> FDA failed to consider the benefits of granular psyllium 
products.

The comment contended that psyllium laxatives in granular dosage form 
are preferred by millions of consumers over powder and other forms, are 
the most widely used laxative drugs in the world, and have provided 
safe and effective relief for many years. The comment submitted an 
article (Ref. 3) that reported a clinical study comparing psyllium-
containing products in granular and powder dosage forms in constipated 
subjects. In the study, the psyllium plus senna combination product in 
granular dosage form was significantly superior to the psyllium-only 
product in powder dosage form with respect to stool frequency, moisture 
content, and weight.
    <bullet> FDA should consider foreign safety data.

The comment submitted listings of suspected foreign cases of dysphagia 
(difficulty in swallowing) associated with the use of its two psyllium 
laxative products in granular dosage form from 1980 to 2003 (Refs. 4 
and 5). The comment reported three serious, and five nonserious, cases 
for the company's psyllium plus senna laxative in granular dosage form 
and six serious, and two

[[Page 14671]]

nonserious, cases for the company's psyllium-only laxative in granular 
dosage form. None of these cases resulted in serious injury or death.
    (Response) FDA disagrees that its analysis overstated the risks of 
psyllium products in granular dosage form. While the number of adverse 
events reports of esophageal blockage associated with psyllium 
laxatives in granular dosage form is low relative to the number of 
doses taken, many of the reports describe serious medical consequences. 
Of the 78 reports of esophageal obstruction and choking-related events 
associated with psyllium laxatives in granular dosage form, 59 required 
hospitalization or medical intervention, including endoscopic 
procedures to remove blockages (68 FR 46133 at 46134). The 
manufacturer's claim that 1 death among 78 adverse events indicates the 
relative safety of the company's granular dosage form product ignores 
the fact that these 78 events represent most of the 98 total events of 
esophageal obstruction associated with all dosage forms containing 
psyllium reported between 1966 and 2000 (68 FR 46133 at 46134).
    Although the comment claims that 17 case reports of esophageal 
obstruction from 1989 to 2000 should not be considered a basis for 
increased safety concern, FDA believes that reports of 44 adverse 
events related to esophageal obstruction reported between January 1999 
and May 2002 (68 FR 46133 at 46135) does provide this basis. In 1993, 
FDA required labeling for all products containing water-soluble gums, 
including psyllium, to include a warning of possible esophageal 
obstruction and directions to take adequate fluid. Many of these recent 
events occurred even though the users had complied with the label 
directions. Thus, FDA has concerns that the problem of esophageal 
obstruction cannot be addressed through labeling. In addition, these 
adverse events are probably significantly underreported. OTC drugs 
without approved applications were not subject to mandatory reporting 
requirements, prior to the enactment of the Dietary Supplement and 
Nonprescription Drug Consumer Protection Act (S. 3546), which was 
signed by the President on December 22, 2006, and voluntary submission 
of reports by health professionals normally account for only about 10 
percent of all reports in FDA's spontaneous reporting system. Under S. 
3546, which amends the Federal Food, Drug, and Cosmetic Act, 
manufacturers, packers, or distributors of certain nonprescription 
drugs must report serious adverse events to FDA.
    FDA acknowledges the occurrence of esophageal obstruction and 
choking-related events associated with psyllium laxatives in 
nongranular dosage forms. In 2000, FDA reviewed reports from its 
adverse event reporting system (AERS) database and the medical 
literature for esophageal obstruction and choking-related events 
associated with psyllium laxatives in all dosage forms, not granular 
dosage forms alone (Ref. 6). This review found 98 total adverse events. 
Of the four deaths reported, only one death was related to a psyllium 
laxative in a granular dosage form, swallowed unchewed with liquid. 
However, significantly more esophageal obstruction and choking-related 
events (78 out of 98) were associated with the granular dosage form 
compared to the powder or wafer dosage form (68 FR 46133 at 46135), and 
these events frequently required medical intervention (59 out of 78). 
Only 13 out of the 98 choking-related and esophageal obstruction events 
were reported for a leading psyllium laxative in powder dosage form. 
Only 2 of these 13 events were confirmed cases of esophageal 
obstruction, where a mass blocking the esophagus was actually 
visualized. The two events involved subjects who, along with a psyllium 
laxative in powder dosage form, took an additional medicine (contrast 
medium tablets or a pain relief caplet), which was later found in the 
blocking mass. In comparison, most of the events associated with the 
psyllium laxatives in granular dosage form (59 out of 78) were 
confirmed cases of esophageal obstruction, requiring medical 
intervention to relieve the obstruction. None of the esophageal 
obstruction cases associated with psyllium laxatives in granular dosage 
form mentioned an additional medicine being taken as a complicating 
factor.
    FDA subsequently requested an update of adverse events associated 
with psyllium laxatives in granular dosage form from a major 
manufacturer of these products. This manufacturer reported 43 events of 
esophageal obstruction associated with the company's psyllium products 
in granular dosage form occurring between January 1999 and January 2001 
(Ref. 7). In May 2002, FDA searched the AERS database for events of 
esophageal obstruction that had occurred since the previous search in 
October 2000, and found one additional event caused by this same 
psyllium product in granular dosage form (Ref. 8). These more recent 
events occurred despite labeling changes initiated by the manufacturer, 
as well as labeling required by FDA (Sec.  201.319).
    FDA concludes that this safety risk posed by psyllium laxatives in 
granular dosage form outweighs the benefits of these products. To 
support its claim that FDA failed to consider the benefits of psyllium 
laxatives in granular dosage form, the comment contended that granular 
dosage forms are preferred by consumers over powder and other forms. 
However, many other OTC laxative drug products are available that have 
the same purpose as psyllium products in granular dosage form but 
without the associated danger of esophageal obstruction.
    FDA finds that the study by Marlett et al. (Ref. 3) submitted by 
the comment does not contribute any new data to support the safety of 
psyllium laxative products in granular dosage form. The article reports 
the results of a placebo-controlled, single-blind study comparing the 
effectiveness of two psyllium-containing laxatives, a granular dosage 
form containing psyllium plus senna and a powder dosage form containing 
psyllium only. FDA believes that any results suggesting that the 
granular dosage form is more effective than the powder dosage form are 
confounded by the comparison of products with different active 
ingredients--psyllium plus senna combined versus psyllium only. FDA 
reviewed the study for information relating to product safety. Only a 
few nonserious adverse events are reported for either treatment group. 
The small number of subjects (42) precludes any conclusions about the 
safety of either formulation in the general population.
    FDA concludes that the submitted foreign safety data (Refs. 4 and 
5), a total of 16 events that occurred outside the United States since 
1980, do not add any significant evidence to support the safety of 
psyllium laxatives in granular dosage form. The comment reported three 
serious and five nonserious cases of dysphagia and/or esophageal 
obstruction following use of the company's psyllium and senna 
combination product in granular dosage form. The comment also reported 
six serious and two nonserious events for its psyllium-only product in 
granular dosage form. According to the comment, none of these events 
resulted in death or serious injury, and all of the people recovered. 
The comment claims these products are leading laxatives in Europe and 
this small number of serious adverse events demonstrates their safety. 
FDA finds the data inadequate to make any conclusion on safety. 
Further, FDA believes the data collected within the United States 
provides sufficient

[[Page 14672]]

basis for a safety concern, without the need for additional 
consideration of foreign safety data.

III. FDA's Final Conclusions on OTC Laxative Products in Granular 
Dosage Form Containing Psyllium Ingredients

    FDA finds that OTC laxative drug products in granular dosage form 
containing psyllium present an unnecessary risk of esophageal 
obstruction and choking. These serious medical emergencies continue to 
occur despite previous measures taken to promote safe use of these 
products, including required warning and direction statements in Sec.  
201.319 for all OTC drug products containing water-soluble gums, 
hydrophilic gums, or hydrophilic mucilloids as active ingredients, 
including psyllium ingredients in granular dosage form. These 
statements instruct consumers to take adequate fluid and to avoid using 
the product if the person has previously experienced any difficulty in 
swallowing.
    FDA is reclassifying bulk laxatives in granular dosage form 
containing psyllium ingredients from Category I (monograph) to Category 
II (nonmonograph). FDA is adding granular dosage forms containing 
psyllium ingredients to Sec.  310.545(a)(12)(i) (21 CFR 
310.545(a)(12)(i)), which lists those active ingredients currently 
without adequate data to establish general recognition of safety and 
effectiveness as a bulk laxative. Concurrently, FDA is revising Sec.  
201.319 to specifically exclude laxative drug products in granular 
dosage form containing psyllium ingredients. FDA concludes that the 
warnings and directions statements required in Sec.  201.319 are not 
adequate to provide for the safe and effective use of psyllium products 
in granular dosage form. This final rule applies to OTC psyllium 
laxative drug products in granular dosage form that include, but are 
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.
    Part of an August 5, 2003, proposed rule for OTC laxative drug 
products proposes to exclude psyllium ingredients when contained in 
granular dosage forms from the list of GRASE bulk-forming psyllium 
laxative active ingredients in Sec.  334.10 (21 CFR 334.10). We will 
finalize this part of the proposed rule to exclude psyllium ingredients 
when we publish the final monograph for OTC laxative drug products.
    Accordingly, any OTC laxative drug product in granular dosage form 
that contains psyllium is considered not GRASE and misbranded under 
section 502 of the act (21 U.S.C. 352). This type of drug product is 
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 (21 CFR 
part 314), is required for marketing. This final rule applies to any 
OTC psyllium-containing laxative drug product in granular dosage form 
that is initially introduced or initially delivered for introduction 
into interstate commerce after the effective date of this final rule. 
Further, any OTC drug product that was previously initially introduced 
or initially delivered for introduction into interstate commerce cannot 
then be repackaged or relabeled after the effective date of this final 
rule.

IV. Analysis of Impacts

    In accordance with Executive Order 12866, FDA has previously 
analyzed the potential economic effects of this final rule (68 FR 46133 
at 46136). As announced in the proposal, the agency has determined that 
the rule is not a significant regulatory action as defined by the 
Order. The agency has not received any new information or comments that 
would alter its previous determination.
    FDA has examined the impacts of this final rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is not a significant regulatory action under the 
Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of the 
rule on small entities. Because of the limited number of products 
affected by this final rule, FDA does not believe that the final rule 
would have a significant economic impact on a substantial number of 
small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $122 million, using the most current (2005) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The purpose of this final rule is to establish conditions under 
which OTC bulk-forming laxatives in granular dosage form containing 
psyllium ingredients are not generally recognized as safe and 
effective. At the time this rule was proposed, FDA's drug listing 
system (DLS) identified nine marketed OTC laxative drug products in 
granular dosage form containing psyllium ingredients, and FDA was aware 
of at least one other product not in its DLS. One manufacturer marketed 
three stock keeping units (SKUs) (individual products, packages, and 
sizes) of the granular dosage form. This manufacturer has since 
reformulated its products and, therefore, will not incur any new costs 
under this final rule. Two manufacturers marketed two SKUs each, and 
one manufacturer marketed one SKU. This final rule will result in the 
reformulation or removal of probably less than 10 products.
    <bullet> 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 current good 
manufacturing practice, and, for some dosage forms, conduct 
palatability tests. (See section 501(a)(2)(B) of the act (21 U.S.C. 
351(a)(2)(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

[[Page 14673]]

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. Also, 
the major U.S. manufacturer of psyllium laxatives in granular dosage 
form has already reformulated its products and will not incur any new 
costs due to this final rule. 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 bulk-forming 
psyllium laxatives in granular dosage form would most likely lead all 
manufacturers to move to alternative products over time.
    <bullet> 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 approximately three SKUs will need to be relabeled 
as a result of reformulation. If these SKUs are relabeled, the total 
one-time cost of relabeling is about $9,000 (three SKUs x $3,000) to 
$15,000 (three SKUs x $5,000). This relabeling cost should not be a 
significant economic impact on a substantial number of small entities.
    Some manufacturers may choose to submit an NDA deviation for their 
psyllium product in accordance with 21 CFR 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 
pharmaceutical current good manufacturing practices (21 CFR parts 210 
and 211), all firms currently have the necessary skills and personnel 
to perform the tasks of reformulation, validation, and relabeling 
either in-house or by contractual arrangement. This rule will not 
require any new reporting and recordkeeping activities. No additional 
professional skills are needed.
    <bullet> Regulatory Alternatives Considered
    FDA considered but rejected the following alternatives: (1) Leave 
these products in the monograph, and (2) an exemption from coverage for 
small entities. FDA does not believe that these or other alternatives 
to this final rule would adequately provide for the safe use of these 
OTC drug products.
    Based on the foregoing, FDA does not believe that this final 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 final regulatory flexibility analysis.

V. Paperwork Reduction Act of 1995

    FDA concludes that any relabeling required by this final 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 final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
will have a preemptive effect on State law. Section 4(a) of the 
Executive order requires agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' Section 751 of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 379r) is an express preemption 
provision. Section 751(a) of the act (21 U.S.C. 379r(a)) provides that:

    * * * no State or political subdivision of a State may establish 
or continue in effect any requirement-- * * * (1) that relates to 
the regulation of a drug that is not subject to the requirements of 
section 503(b)(1) or 503(f)(1)(A); and (2) that is different from or 
in addition to, or that is otherwise not identical with, a 
requirement under this Act, the Poison Prevention Packaging Act of 
1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling 
Act (15 U.S.C. 1451 et seq.). * * *

Currently, this provision operates to preempt States from imposing 
requirements related to the regulation of nonprescription drug 
products. (See Section 751(b) through (e) of the act for the scope of 
the express preemption provision, the exemption procedures, and the 
exceptions to the provision.) This final rule will establish that OTC 
laxative drug products in granular dosage form containing bulk-forming 
psyllium ingredients are not GRASE and are misbranded. Although this 
final rule would have a preemptive effect, in that it would preclude 
States from promulgating requirements related to OTC laxative drug 
products in granular dosage form containing psyllium ingredients that 
are different from or in addition to, or not otherwise identical with 
the requirements in this final rule, this preemptive effect is 
consistent with what Congress set forth in section 751 of the act. 
Section 751(a) of the act displaces both State legislative requirements 
and State common law duties. We also note that even where the express 
preemption provision is not applicable, implied preemption may arise. 
See Geier v. American Honda Co., 529 US 861 (2000).
    FDA believes that the preemptive effect of the final rule would be 
consistent with Executive Order 13132. Section 4(e) of the Executive 
order provides that ``when an agency proposes to act through 
adjudication or rulemaking to preempt State law, the agency shall 
provide all affected State and local officials notice and an 
opportunity for appropriate participation in the proceedings.'' FDA 
provided the States with an opportunity for appropriate participation 
in this rulemaking when it sought input from all stakeholders through 
publication of the proposed rule in the Federal Register of August 5, 
2003 (68 FR 46133). FDA received no comments from any States on the 
proposed rulemaking.
    In addition, on February 13, 2007, FDA's Division of Federal and 
State Relations provided notice via fax and e-mail transmission to 
elected officials of State governments and their representatives of 
national organizations. The notice provided the States with further 
opportunity for input on the rule. It advised the States of the 
publication of the August 5, 2003, proposed rule and encouraged State 
and

[[Page 14674]]

local governments to review the notice and to provide any comments to 
the docket (Docket No. 1978N-0036L) by a date 30 days from the date of 
the notice (i.e., by March 14, 2007), or to contact certain named 
individuals. FDA received no comments in response to this notice. The 
notice has been filed in Docket No. 1978N-0036L.
    In conclusion, FDA believes that it has complied with all of the 
applicable requirements under the Executive order and has determined 
that the preemptive effects of this rule are consistent with Executive 
Order 13132.

VIII. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES), under Docket No. 1978N-0036L, and may be 
seen by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday.
    1. 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.
    2. Comment No. C00206, Attachment 1.
    3. Comment No. C00206, Attachment 3.
    4. Comment No. C00206, Attachment 4.
    5. Comment No. C00206, Attachment 5.
    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. 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 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 310

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

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
201 and 310 are amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

0
2. Section 201.319 is amended by revising paragraph (a) to read as 
follows:


Sec.  201.319  Water-soluble gums, hydrophilic gums, and hydrophilic 
mucilloids (including, but not limited to agar, alginic acid, calcium 
polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, 
glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, 
kelp, methylcellulose, plantago seed (psyllium), polycarbophil, 
tragacanth, and xanthan gum) as active ingredients; required warnings 
and directions.

    (a) Reports in the medical literature and data accumulated by the 
Food and Drug Administration indicate that esophageal obstruction and 
asphyxiation have been associated with the ingestion of water-soluble 
gums, hydrophilic gums, and hydrophilic mucilloids including, but not 
limited to, agar, alginic acid, calcium polycarbophil, 
carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-
1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, 
methylcellulose, plantago seed (psyllium), polycarbophil, tragacanth, 
and xanthan gum. Esophageal obstruction and asphyxiation due to orally-
administered drug products containing water-soluble gums, hydrophilic 
gums, and hydrophilic mucilloids as active ingredients are significant 
health risks when these products are taken without adequate fluid or 
when they are used by individuals with esophageal narrowing or 
dysfunction, or with difficulty in swallowing. Additional labeling is 
needed for the safe and effective use of any OTC drug product for human 
use containing a water-soluble gum, hydrophilic gum, or hydrophilic 
mucilloid as an active ingredient when marketed in a dry or 
incompletely hydrated form to include, but not limited to, the 
following dosage forms: Capsules, granules, powders, tablets, and 
wafers. Granular dosage forms containing psyllium are not generally 
recognized as safe and effective as OTC laxatives (see Sec.  
310.545(a)(12)(i)(B) of this chapter) and may not be marketed without 
an approved new drug application because the warnings and directions in 
paragraph (b) of this section have been found inadequate for these 
products.
* * * * *

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 redesignating paragraph (a)(12)(i) as 
paragraph (a)(12)(i)(A), by adding paragraph (a)(12)(i)(B), by revising 
paragraph (d) introductory text and paragraph (d)(1), and by adding 
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 March 29, 2007.
Granular dosage forms containing psyllium (hemicellulose), psyllium 
hydrophilic mucilloid, psyllium seed, psyllium seed (blond), psyllium 
seed husks, plantago husks, or plantago seed 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), (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), (a)(18)(iii), (a)(18)(iv), (a)(18)(v)(A), and 
(a)(18)(vi)(A) of this section.
* * * * *
    (38) October 1, 2007, for products subject to paragraph 
(a)(12)(i)(B) of this section.

    Dated: March 20, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-5740 Filed 3-28-07; 8:45 am]
BILLING CODE 4160-01-S[FEDREG][VOL]*[/VOL][NO]*[/NO][DATE]*[/
DATE][RULES]