[Federal Register: May 9, 2002 (Volume 67, Number 90)]
[Rules and Regulations]               
[Page 31125-31127]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



Food and Drug Administration

21 CFR Part 310

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

Status of Certain Additional Over-the-Counter Drug Category II 
and III Active Ingredients

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.


SUMMARY:  The Food and Drug Administration (FDA) is issuing a final 
rule stating that the stimulant laxative ingredients aloe (including 
aloe extract and aloe flower extract) and cascara sagrada (including 
casanthranol, cascara fluidextract aromatic, cascara sagrada bark, 
cascara sagrada extract, and cascara sagrada fluidextract) in over-the-
counter (OTC) drug products are not generally recognized as safe and 
effective or are misbranded. This final rule is part of FDA's ongoing 
OTC drug product review.

DATES:  This rule is effective November 5, 2002.

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


I. Background

    In the Federal Register of November 7, 1990 (55 FR 46914), FDA 
published under 21 CFR 330.10(a)(7)(ii) a final rule on the status of 
certain OTC drug category II and III active ingredients. That final 
rule declared as not generally recognized as safe and effective certain 
active ingredients that had been proposed as nonmonograph (category II 
or III) under the agency's OTC drug review. The periods for submission 
of comments and new data following the publication of a notice of 
proposed rulemaking had closed and no significant comments or new data 
had been submitted to upgrade the status of these ingredients. In each 
instance, a final rule for the class of ingredients involved had not 
been published to date.
    In the Federal Register of June 19, 1998 (63 FR 33592), FDA 
reopened the administrative record and reclassified the stimulant 
laxative ingredients aloe, bisacodyl, cascara sagrada (including 
casanthranol, cascara fluidextract aromatic, cascara sagrada bark, 
cascara sagrada extract, and cascara sagrada fluidextract), and senna 
(including sennosides A and B) from category I (monograph) to category 
III (more data needed). The agency requested mutagenicity, 
genotoxicity, and carcinogenicity data on aloe and cascara sagrada 
ingredients and carcinogenicity data on bisacodyl and senna. The agency 
recommended that persons interested in testing these drugs consult the 
agency before initiating any studies and stated that these ingredients 
would be placed in category II (nonmonograph) in a final rule if data 
were not provided. The agency has received data on bisacodyl and senna, 
which will be discussed in future issues of the Federal

[[Page 31126]]

Register. However, no comments or data were submitted for aloe or 
cascara sagrada ingredients.
    Accordingly, aloe and cascara sagrada ingredients will not be 
included in the final monograph for OTC laxative drug products because 
they have not been shown to be generally recognized as safe and 
effective for their intended use. These ingredients should be 
eliminated from OTC laxative drug products 180 days after the date of 
publication of this final rule, regardless of whether further testing 
is undertaken to justify future use.
    The agency points out that publication of this final rule does not 
preclude a manufacturer's testing an ingredient. New, relevant data can 
be submitted to the agency at a later date as the subject of a new drug 
application that may provide for prescription or OTC marketing status. 
(See part 314 (21 CFR part 314).) As an alternative, where there are 
adequate data establishing general recognition of safety and 
effectiveness, such data may be submitted in an appropriate citizen 
petition to amend a monograph. (See Sec. 10.30 (21 CFR 10.30).)

II. The Agency's Final Conclusions

    Based on the lack of data and information and the failure of 
interested persons to submit any new data from carcinogenicity studies, 
the agency has determined that the stimulant laxative ingredients aloe 
(including aloe extract and aloe flower extract) and cascara sagrada 
(including casanthranol, cascara fluidextract aromatic, cascara sagrada 
bark, cascara sagrada extract, and cascara sagrada fluidextract) should 
be deemed not generally recognized as safe and effective for OTC use 
before a final monograph is established for OTC laxative drug products. 
The agency is reclassifying these ingredients to category II 
(nonmonograph) and is adding them to the list of stimulant laxative 
ingredients for which the data are inadequate to establish general 
recognition of safety and effectiveness for such use in 
Sec. 310.545(a)(12)(iv) (21 CFR 310.545(a)(12)(iv)) at new 
Sec. 310.545(a)(12)(iv)(C).
    Accordingly, any drug product containing any of these aloe or 
cascara sagrada ingredients and labeled for OTC laxative use will be 
considered nonmonograph and misbranded under section 502 of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352) and 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 
part 314 of the regulations is required for marketing. This applies to 
any OTC drug product containing any of these aloe or cascara sagrada 
ingredients and labeled for laxative use 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 be repackaged or relabeled 
after the effective date of the rule. Manufacturers are encouraged to 
comply voluntarily with the rule at the earliest possible date.

III. Analysis of Impacts

    FDA has examined the impacts of this final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121)), 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 agency concludes that this final rule is consistent with the 
principles set out in the Executive order and in these two statutes. In 
accordance with Executive Order 12866, FDA previously analyzed the 
potential economic effects of this final rule. As stated in the 
proposal (63 FR 33592 at 33594), the agency believed then that the rule 
would not be a significant regulatory action as defined by the 
Executive order. The agency has not received any new information or 
comments altering its previous expectations. Further, since this final 
rule is not expected to result in any 1-year expenditure that would 
exceed $100 million adjusted for inflation, FDA need not prepare 
additional analyses under the Unfunded Mandates Reform Act.
    The purpose of this final rule is to act on the nonmonograph status 
of certain stimulant laxative ingredients in advance of finalization of 
other monograph conditions in order to expedite completion of the OTC 
drug review. Products containing these ingredients will need to be 
reformulated to delete and/or replace the ingredient(s) with another 
laxative active ingredient. There are a number of acceptable laxative 
active ingredients in proposed part 334 (50 FR 2124 at 2152, January 
15, 1985) that could be used. The reformulated products will also 
require relabeling.
    The agency's Drug Listing System (DLS) identifies approximately 15 
OTC laxative drug products that contain aloe (including aloe extract 
and aloe flower extract) and 160 OTC laxative drug products that 
contain cascara sagrada ingredients. Six products contain both aloe and 
cascara or casanthranol and appear on both lists. Approximately 125 
products contain casanthranol and docusate sodium, a proposed monograph 
laxative ingredient. These combination products could be reformulated 
to eliminate the casanthranol, replace the casanthranol with sennosides 
A and B or sodium carboxymethylcellulose (proposed monograph 
combinations with docusate sodium in Sec. 334.30(i)(3) and (j) (58 FR 
46589 at 46595, September 2, 1993)), or possibly increase the quantity 
of docusate sodium in the product, in conformance with the proposed 
    The cost to reformulate a product will vary greatly, based on: The 
nature of the change in formulation, the product, the process, and the 
size of the firm. Based on the reformulation options discussed 
previously in this document, most firms should not need to change their 
dosage form. However, they 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 DLS indicates that approximately 35 manufacturers and 70 
distributors/repackers/relabelers market these 170 products. Most firms 
have only one or two products and should not incur substantial economic 
expense should they choose to reformulate or discontinue their 
product(s). The 35 manufacturers will incur the majority of the costs 
to reformulate and relabel products.

[[Page 31127]]

    The agency estimates the range of reformulation costs is from 
$100,000 to $500,000 per product. As most affected firms have only one 
or two products containing these ingredients, the midpoint of the cost 
estimate for reformulation implies total costs of $300,000 to $600,000 
per firm. If all manufacturers decide to reformulate, about 56 products 
would be affected. Using the midpoint of the estimated cost to 
reformulate ($300,000) implies total costs of $16.8 million. However, 
the agency believes the total costs will be lower because not all firms 
will choose to reformulate. Some firms may choose to discontinue a 
product line if sales are too low to justify the added cost of 
reformulation and/or they may place their market emphasis on other OTC 
laxative drug products. The lost sales from the products containing 
nonmonograph ingredients may be offset by sales of the substitute 
products containing monograph ingredients. In addition, firms have been 
aware of the proposed nonmonograph status of these products since 1998 
and have not submitted data to the agency. While this final rule may 
cause firms to discontinue marketing or to reformulate some products 
prior to issuance of the final monograph, these firms have known for 
some time that if adequate data were not submitted to support safety, 
cessation of marketing of the current products would be required, in 
any event, when the final monograph is published.
    The agency estimates that the average cost to relabel OTC drug 
products is about $3,600. The agency is unsure of how many products 
will require new labeling. If all of the 170 products are reformulated 
and are still marketed, then the one-time costs to relabel would be 
$612,000. The estimated total one-time reformulation and relabeling 
cost would be $17.8 million.
    The agency considered but rejected not acting on these ingredients 
in advance of the finalization of other monograph conditions. As firms 
have not submitted the requested safety data, these ingredients will 
not be included in the final monograph when completed. The agency has 
determined that there is no reason to allow continued marketing of OTC 
laxative drug products containing any of these ingredients. Consumers 
will benefit from the early removal from the marketplace of products 
containing ingredients for which safety has not been established. 
Consumers can then purchase products containing only ingredients 
proposed for monograph status. Manufacturers who choose to reformulate 
or replace affected products will be able to use alternate ingredients, 
as discussed previously in this document, that are proposed as 
monograph conditions without incurring any additional expense of 
clinical testing for those ingredients.
    Because these products must be manufactured in compliance with the 
pharmaceutical current good manufacturing practices (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. No additional professional skills are 
needed. No other Federal rules duplicate, overlap, or conflict with 
this rule.
    The agency has considered the burden to small entities and 
identified reformulation options available to them. Nevertheless, some 
entities may incur significant impacts, especially private label 
manufacturers that provide labeling for a number of the affected 
products. 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.

IV. Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

V. 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.

VI. 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 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.

List of Subjects in 21 CFR Part 310

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

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


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

    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, 
    2. Section 310.545 is amended by adding paragraphs (a)(12)(iv)(C) 
and (d)(30) to read as follows:

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

    (a) * * * 
    (12) * * * 
    (iv)(C) Stimulant laxatives--Approved as of November 5, 2002.
Aloe ingredients (aloe, aloe extract, aloe flower extract)
Cascara sagrada ingredients (casanthranol, cascara fluidextract 
aromatic, cascara sagrada bark, cascara sagrada extract, cascara 
sagrada fluidextract).
* * * * *
    (d) * * * 
    (30) November 5, 2002, for products subject to paragraph 
(a)(12)(iv)(C) of this section.
* * * * *

    Dated: April 29, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-11510 Filed 5-8-02; 8:45 am]