[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
