[Federal Register Volume 63, Number 118 (Friday, June 19, 1998)]
[Proposed Rules]
[Pages 33592-33595]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-16290]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 334

[Docket No. 78N-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: Notice of proposed rulemaking.

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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 stimulant laxative ingredients aloe, 
bisacodyl, cascara sagrada, and senna (including sennosides A and B) 
from Category I (generally recognized as safe and effective and not 
misbranded) to Category III (further testing is required). FDA is 
issuing this proposed rulemaking after considering data and information 
on the safety of bisacodyl, senna, and two related stimulant laxative 
ingredients, danthron and phenolphthalein. This proposal is part of the 
ongoing review of OTC drug products conducted by FDA.
DATES: Submit written comments by September 17, 1998. Written comments 
on the agency's economic impact determination by September 17, 1998. 
New data by June 21, 1999. Comments on the new data by August 19, 1999.
ADDRESSES: Submit written comments and new data to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857.

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

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of March 21, 1975 (40 FR 12902), FDA 
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance 
notice of proposed rulemaking to establish a monograph for OTC 
laxative, antidiarrheal, emetic, and antiemetic drug products, together 
with the recommendations of the Advisory Review Panel on OTC Laxative, 
Antidiarrheal, Emetic, and Antiemetic Drug Products (the Panel), which 
was the advisory review panel responsible for evaluating data on the 
active ingredients in these classes. In the advance notice of proposed 
rulemaking, the Panel recommended Category I status for the OTC 
stimulant laxative ingredients aloe, bisacodyl, cascara sagrada 
preparations, danthron, phenolphthalein, and senna preparations (40 FR 
12902 at 12908 to 12910). The agency concurred with the Panel's 
Category I classification of these ingredients in the tentative final 
monograph published in the Federal Register of January 15, 1985 (50 FR 
2124 at 2152 to 2156).

II. Danthron and Phenolphthalein

    In the Federal Register of September 2, 1997 (62 FR 46223), the 
agency reopened the administrative record for this rulemaking, 
discussed the carcinogenic risk of danthron and phenolphthalein, and 
proposed to reclassify these two anthraquinone laxative ingredients 
from Category I to Category II (not generally recognized as safe and 
effective or misbranded). The agency is evaluating the data and 
comments submitted in response to that proposal and will discuss this 
subject further in a future issue of the Federal Register.

III. Bisacodyl

    The FDA Center for Drug Evaluation and Research (CDER) 
Carcinogenicity Assessment Committee (CAC) has recommended that the 
anthraquinone laxatives (aloe, cascara sagrada, and senna) and 
bisacodyl be tested in the standard battery of genotoxicity tests and 
under the test conditions by which phenolphthalein was found to be 
positive (Ref. 1). Phenolphthalein and bisacodyl are diphenylmethane 
derivatives with a similar chemical structure and pharmacological 
characteristics. The CAC recommended the Syrian Hamster Embryo (SHE) 
cell transformation assay as an early screen for bisacodyl and, based 
on its results, either the p53 transgenic mouse assay or another in 
vivo alternative assay, as appropriate, follow. Two-year 
carcinogenicity studies would then be contingent upon the results of 
these assays.
    The agency has informed industry that additional testing for 
bisacodyl will be necessary (Ref. 2). Subsequently, industry submitted 
data from two mutagenicity studies (Ames test and rat bone marrow 
micronucleus assay) and a chromosomal aberration study in Chinese 
hamster ovary cells. The agency has reviewed these studies and 
determined that the results of all of the tests were negative (Ref. 3). 
Phenolphthalein was tested in two of these tests and was found negative 
in one (Ames test). However, findings from further studies indicated 
that phenolphthalein presents a potential carcinogenic risk. Thus, 
because of the chemical similarity of bisacodyl to phenolphthalein and 
the lack of previous carcinogenicity testing of bisacodyl, the agency 
is requesting that bisacodyl undergo further testing to assess its 
carcinogenic potential. Industry has completed dose range finding 
studies intended to select bisacodyl doses for a 6-month oral gavage 
carcinogenicity study in the p53 transgenic mouse (Ref. 4).

IV. Senna

    The agency has reviewed metabolic, genotoxicity, and 
carcinogenicity data on senna and its components (Ref. 5). Senna 
contains a number of components, including but not limited to: 
Sennosides A and B, sennosides C and D, rhein (including rhein 
anthrone-8-monoglucoside and rhein-8-monoglucoside), chrysophanol, 
emodin, and aloe-emodin. The metabolic studies show that varying 
amounts of senna and its metabolites are absorbed into the

[[Page 33593]]

systemic circulation. The data do not present conclusive absorption 
information, nor indicate whether any of the metabolites present a 
safety hazard, if absorbed.
    The agency believes that there are sufficient mutagenicity (Ames 
test) data in the literature on the senna extracts sennosides A and B, 
aloe-emodin, chrysophanol, and emodin. The data indicate that 
sennosides A and B are negative, while the senna extracts aloe-emodin, 
emodin, and chrysophanol are positively genotoxic (Ref. 5). Thus, senna 
preparations containing any of these components (or kaempferol or 
quercetin) may have mutagenic properties. These potentially mutagenic 
anthrones are found in the dried leaves and pods of senna. Therefore, 
until manufacturers can show that commercially available senna 
preparations do not contain mutagenic/genotoxic components, the agency 
is unable to state that sennosides A and B do not pose a relative risk 
to humans.
    The agency also reviewed a 2-year carcinogenicity study with 
sennosides in the rat (Ref. 6). However, the agency found this study 
deficient because of the limited and incomplete histopathologic 
examination of tissues (Ref. 5). The agency concludes that further 
testing is necessary to assess the carcinogenic potential of senna 
products. In these studies, specific analysis of the test substance 
should be done to enable quantitative estimation of each component of 
the preparation. The senna dose selection should be based on a 1-month 
dose ranging study for an alternative assay or a 3-month dose ranging 
study for a 2-year carcinogenicity study in the rodent species and 
strains selected for the carcinogenicity studies. Histopathologic 
examination of all tissues from all groups of animals should be 
conducted (Ref. 5).

V. Aloe and Cascara Sagrada Preparations

    Aloe and cascara sagrada are other anthraquinone ingredients. 
Cascara sagrada ingredients included in the tentative final monograph 
are casanthranol, cascara fluidextract aromatic, cascara sagrada bark, 
cascara sagrada extract, and cascara sagrada fluidextract (50 FR 2124 
at 2152). The agency has not received any mutagenicity, genotoxicity, 
or carcinogenicity data for these ingredients. The agency concludes 
that these ingredients need to have these types and other toxicity data 
using tests similar to those used and found positive for 
phenolphthalein.

VI. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Comment No. MM13, Docket No. 78N-036L, Dockets Management 
Branch.
    2. Letter from D. Bowen, FDA, to R. W. Soller, Nonprescription 
Drug Manufacturers Association (NDMA), coded LET111, Docket No. 78N-
036L, Dockets Management Branch.
    3. Letter from D. Bowen, FDA, to L. Totman, NDMA, coded LET175, 
Docket No. 78N-036L, Dockets Management Branch.
    4. Comment No. C178, Docket No. 78N-036L, Dockets Management 
Branch.
    5. Letter from D. Bowen, FDA, to J. Conover, The Purdue 
Frederick Co., coded LET173, Docket No. 78N-036L, Dockets Management 
Branch.
    6. Comment No. LET113, Docket No. 78N-036L, Dockets Management 
Branch.

VII. Summary of the Agency's Changes to the Proposed Rule

    The agency is proposing to reclassify the stimulant laxative 
ingredients aloe, bisacodyl, cascara sagrada (including casanthranol), 
and senna (including sennosides A and B) from Category I (monograph) to 
Category III (more data needed). The agency recommends that persons 
interested in testing these drugs consult the agency about 
carcinogenicity study requirements and protocols before initiating any 
studies. If these data are not provided or are inadequate for any of 
these ingredients, these ingredients will be placed in Category II 
(nonmonograph) in a final rule. The agency will add any of these 
ingredients that become nonmonograph to the list of stimulant laxatives 
in Sec. 310.545(a)(12)(iv) (21 CFR 310.545(a)(12)(iv)) in new 
Sec. 310.545(a)(12)(iv)(C). The agency will also amend proposed 
Secs. 334.18, 334.30, 334.32, 334.60, 334.66, and 334.80 to remove any 
of these ingredients and their labeling if any of these ingredients are 
not included in the final monograph.

VIII. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
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.
    Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et 
seq.) requires that agencies prepare a written statement and economic 
analysis before proposing any rule that may result in an expenditure in 
any 1 year by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million (adjusted annually for 
inflation).
    The agency believes that this proposed rule is consistent with the 
principles set out in the Executive Order and in these two statutes. 
The purpose of this proposed rule is to establish conditions under 
which the OTC stimulant laxative ingredients aloe, bisacodyl, cascara 
sagrada, and senna are or are not generally recognized as safe and 
effective. If the ingredients are determined to be safe and effective, 
no product reformulation will be necessary. If the ingredients are not 
determined to be safe and effective, product reformulation will be 
needed. There are a number of other laxative ingredients in proposed 
part 334 (50 FR 2124 at 2152) or one of these ingredients, if found 
safe and effective, that could be used if product reformulation becomes 
necessary.
    The cost to reformulate a product will vary greatly depending on 
the nature of the change in formulation, the product, the process, and 
the size of the firm. Because of the large number of monograph active 
ingredients available for substitution, no manufacturer should need to 
change its dosage form; however, a manufacturer would have to redo the 
validation (product, process, new supplier), conduct stability tests, 
change master production records, and, for some dosage forms, conduct 
palatability tests. Competitive market forces and increased public 
awareness of a potential safety hazard of these ingredients would most 
likely lead all manufacturers to move to alternative products over 
time.
    Manufacturers of these products will also incur costs to relabel 
their products to reflect the new formulation. The agency obtained 
estimates of relabeling costs for the type of changes required by this 
proposed rule ranging from $2,700 to $10,000 per standard stock keeping 
unit (SKU) (individual products, packages, and sizes) for nationally 
branded products and from $500 to $1,500 per SKU for private label 
products. The agency estimates the number of SKU's that will need to be 
relabeled as a result of reformulation as between 500 and 1,000, 
depending if

[[Page 33594]]

some or all of the involved ingredients are not included in the final 
monograph for OTC laxative drug products. Most of these label changes 
will be made by private label manufacturers that tend to use simpler 
and less expensive labeling.
    Finally, some manufacturers that do not reformulate and validate 
their products by the effective date of the final rule may incur a loss 
of revenue. Nevertheless, because of the large number of substitute 
products that are available, many in the same dosage form, there should 
be no significant drop in the overall consumption of laxative drug 
products. Some manufacturers already have other laxative products. If 
products need to be reformulated eventually, manufacturers will be able 
to retain the same brand names. Consumer loyalty to these brands should 
lessen the revenue losses to these firms.
    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. There are no other Federal rules that duplicate, 
overlap, or conflict with this rule.
    Small business impact. The U.S. Small Business Administration 
designates an entity as small if it employs less than 750 employees. 
The agency does not believe that any small firms will be conducting 
genotoxicity or carcinogenicity studies on any of the laxative 
ingredients included in this proposal. Small firms that may have to 
reformulate their products could incur significant costs as a result of 
this rule. The agency is attempting to reduce this burden by keeping 
industry informed of the findings of new research on these products 
through public meetings and letters to manufacturers of products 
containing these ingredients. In this manner, manufacturers should be 
aware of which ingredients are likely to be included or excluded from 
the final monograph and can make their marketing decisions accordingly.
    The agency considered but rejected the following alternatives: (1) 
Fewer testing requirements, and (2) an exemption from coverage for 
small entities. The agency does not consider either of these approaches 
acceptable because they do not assure that consumers will have safe and 
effective OTC laxative drug products at the earliest possible time. The 
agency does not believe that there are any significant alternatives to 
the proposed rule that would adequately provide for the safe and 
effective use of these OTC drug products.
    The agency expects that this proposed rule will not be economically 
significant under Executive Order 12866, nor would it impose an 
Unfunded Mandate (as that term is described in the Unfunded Mandate 
Act). The agency also believes that it is undertaking steps to reduce 
the burden to small entities. Nevertheless, some entities may incur 
significant impacts, especially manufacturers that may have to 
reformulate their products and, to a lesser extent, private label 
manufacturers that provide labeling for a number of the affected 
products. Thus, this economic analysis, together with other relevant 
sections of this document, serves as the agency's initial regulatory 
flexibility analysis, as required under the Regulatory Flexibility Act.
    Finally, the agency specifically invites public comment regarding 
any substantial or significant economic impact that this rulemaking 
would have on OTC laxative drug products containing aloe, bisacodyl, 
cascara sagrada, and senna, particularly the costs associated with 
reformulation. Comments regarding the impact of this rulemaking on OTC 
laxative drug products containing any of these ingredients should be 
accompanied by appropriate documentation. The agency 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.

IX. Paperwork Reduction Act of 1995

    FDA tentatively concludes that labeling requirements related to 
this proposed rule are not subject to review by the Office of 
Management and Budget because they do not constitute a ``collection of 
information'' under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 
et seq.). Rather, this proposed rulemaking involves labeling that is a 
``public disclosure of information originally supplied by the Federal 
government to the recipient for the purpose of disclosure to the 
public'' (5 CFR 1320.3(c)(2)).

X. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that is categorically excluded from the preparation of an 
environmental assessment because these actions, as a class, will not 
result in the production or distribution of any substance and therefore 
will not result in the production of any substance into the 
environment.

XI. Request for Comments

    Interested persons may, on or before September 17, 1998, submit 
written comments on the proposed regulation to the Dockets Management 
Branch (address above). Written comments on the agency's economic 
impact determination may be submitted on or before September 17, 1998. 
Three copies of all comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document and may 
be accompanied by a supporting memorandum or brief. Received comments 
may be seen in the office above between 9 a.m. and 4 p.m., Monday 
through Friday.
    Interested persons may also submit new data demonstrating the 
safety of any of those conditions not classified in Category I on or 
before June 21, 1999. Written comments on the new data may be submitted 
on or before August 19, 1999. Three copies of all data and comments 
should be submitted as stated previously, and received data and 
comments may be seen as stated previously. In establishing a final 
monograph, the agency will ordinarily consider only data submitted 
prior to the closing of the administrative record on August 19, 1999. 
Data submitted after the closing of the administrative record will be 
reviewed by the agency only after a final monograph is published in the 
Federal Register, unless the Commissioner of Food and Drugs finds good 
cause has been shown that warrants earlier consideration.

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), September 2, 1993 (58 FR 
46589), and September 2, 1997 (62 FR 46223)) be amended as follows:

[[Page 33595]]

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, 356, 357, 
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 adding new paragraphs 
(a)(12)(iv)(C) and (d)(30), and by revising paragraph (d) introductory 
text to read as follows:


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

    (a) * * *
    (12) * * *
    (iv)(C) Stimulant laxatives--Approved as of (date of publication in 
the Federal Register).
Aloe
Bisacodyl
Cascara sagrada in any form (e.g., casanthranol, cascara fluidextract 
aromatic, cascara sagrada bark, cascara sagrada extract, cascara 
sagrada fluidextract)
Senna in any form (e.g., senna fluidextract, senna fruit extract, senna 
leaf powder, senna pod concentrate, senna syrup, or sennosides A and B)
 * * * * *
    (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)(30) of this section.
 * * * * *
    (30) (Date 6 months after date of publication in the Federal 
Register), for products subject to paragraph (a)(12)(iv)(C) of this 
section.

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

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

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


Sec. 334.18  [Amended]

    4. Section 334.18 Stimulant laxative active ingredients is amended 
by removing paragraphs (a), (b), (c)(1) through (c)(5), and (f) and 
redesignating paragraphs (d) and (e) as paragraphs (a) and (b), 
respectively.


Sec. 334.30  [Amended]

    5. Section 334.30 Permitted combinations of active laxative 
ingredients is amended by removing and reserving paragraphs (c), (e), 
(g), (h), and (i).


Sec. 334.32  [Amended]

    6. Section 334.32 Bowel cleansing systems is amended by removing 
and reserving paragraph (a).


Sec. 334.60  [Amended]

    7. Section 334.60 Labeling of stimulant laxative drug products is 
amended by removing paragraphs (b)(3), (d)(1) through (d)(7), (d)(10), 
and (d)(11), by removing and reserving paragraph (c), and by 
redesignating paragraphs (d)(8) and (d)(9) as paragraphs (d)(1) and 
(d)(2), respectively.


Sec. 334.66  [Amended]

    8. Section 334.66 Labeling of bowel cleansing systems identified in 
Sec. 334.32 is amended in paragraph (a) by removing ``Sec. 334.32(a)'' 
and adding in its place ``Sec. 334.32''and by removing and reserving 
paragraphs (c)(1) and (d)(3)(iii)(A).


Sec. 334.80  [Amended]

    9. Section 334.80 Professional labeling is amended in paragraph 
(a)(2) by removing the words ``or bisacodyl identified in 
Sec. 334.18(b)'', by removing paragraphs (a)(4) and (c)(5) through 
(c)(10), and by adding the word ``or'' after ``Sec. 334.16(a)'' in 
paragraph (a)(2), and by redesignating paragraphs (c)(11), (c)(12), and 
(c)(13) as paragraphs (c)(5), (c)(6), (c)(7), respectively.

    Dated: June 9, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-16290 Filed 6-18-98; 8:45 am]
BILLING CODE 4160-01-F