[Federal Register Volume 64, Number 19 (Friday, January 29, 1999)]
[Rules and Regulations]
[Pages 4535-4540]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-1938]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 310
[Docket No. 78N-036L]
RIN 0910-AA01
Laxative Drug Products for Over-the-Counter Human Use
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
establishing that the over-the-counter (OTC) stimulant laxative
ingredients danthron and phenolphthalein are not generally recognized
as safe and effective and are misbranded. FDA is issuing this final
rule as part of its ongoing review of OTC drug products after
considering data and information on the safety of danthron and
phenolphthalein.
EFFECTIVE DATE: January 29, 1999.
FOR FURTHER INFORMATION CONTACT: Cheryl A. Turner, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.
SUPPLEMENTARY INFORMATION:
I. Background
In the 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 that evaluated data on the active
ingredients in these classes. In the advance notice of proposed
rulemaking, the Panel recommended Category I (generally recognized as
safe and effective and not misbranded) status for the OTC stimulant
laxative ingredients danthron and phenolphthalein (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).
In the Federal Register of September 2, 1997 (62 FR 46223), FDA
reopened
[[Page 4536]]
the administrative record and proposed to amend the tentative final
monograph for OTC laxative drug products to reclassify danthron and
phenolphthalein from Category I to Category II (not generally
recognized as safe and effective or misbranded) and to add these
ingredients to a list of nonmonograph active ingredients. Interested
persons were invited to submit comments on or before October 2, 1997.
Data and information received after the administrative record was
reopened are on display in the Dockets Management Branch (HFA-305),
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville,
MD 20852.
This final rule declares OTC laxative drug products containing the
active ingredients danthron or phenolphthalein to be new drugs within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 321(p)), for which an application or
abbreviated application (hereinafter called application) approved under
section 505 of the act (21 U.S.C. 355) and 21 CFR part 314 is required
for marketing. In the absence of an approved application, products
containing these drugs for laxative use also would be misbranded under
section 502 of the act (21 U.S.C. 352).
The final rule amends part 310 (21 CFR part 310) to include the
laxative active ingredients danthron and phenolphthalein by adding new
Sec. 310.545(a)(12)(iv)(B). Because a safety problem has been
identified for OTC drug products containing danthron and
phenolphthalein, this final rule is effective on the date of its
publication in the Federal Register. Therefore, on or after January 29,
1999, no OTC drug products that are subject to this final rule may be
initially introduced or initially delivered for introduction into
interstate commerce unless they are the subject of an approved
application.
Nineteen comments were received in response to the proposed rule
on danthron and phenolphthalein. All comments addressed
phenolphthalein. Copies of the comments received are on public display
in the Dockets Management Branch (address above).
II. The Agency's Conclusions on the Comments
1. Three comments agreed that phenolphthalein should be removed
from OTC laxative drug products because of the public health importance
of this matter and the need for prompt closure by FDA. Eight comments
contended that phenolphthalein should remain in OTC laxative drug
products because the National Toxicology Program (NTP) data (Ref. 1)
were insufficient to determine whether phenolphthalein posed a risk to
humans, and because phenolphthalein has been safely and effectively
used for many years. Several consumers indicated that they will not be
able to find another laxative ingredient as effective as
phenolphthalein, and believed that their health will be affected if
they can no longer use phenolphthalein.
As stated in this document, the agency concludes that
phenolphthalein is not safe and not of sufficient medical value to
outweigh the potential risks associated with its OTC use. As there are
at least 25 other laxative ingredients available for OTC use, the
agency concludes that consumers have access to sufficient alternative
laxatives.
2. Four comments offered alternatives to removing phenolphthalein
from OTC laxative drug products. Three comments argued that stronger
warning statements on the phenolphthalein product label and public
education would adequately alert consumers of the potential health risk
to humans and emphasize appropriate use of the drug.
The agency concludes that stronger warning statements and public
education will not change the potential risk of using phenolphthalein
and that this risk is not acceptable given the benefit for laxative use
in the OTC target population.
3. Three manufacturers contended that actual carcinogenic effects
of phenolphthalein in humans have not been determined and recommended
that studies be conducted to evaluate the safe use of phenolphthalein
in humans. One manufacturer stated that these additional data may take
2 to 3 years to obtain and recommended a moratorium on the decision to
remove phenolphthalein from OTC laxative drug products. One
manufacturer offered to conduct a case control human surveillance
safety study. Two manufacturers recommended that FDA or another agency
conduct studies to evaluate the safe use of phenolphthalein in humans.
The agency notes that it is the manufacturer's responsibility to
conduct studies to determine whether phenolphthalein is safe for human
use. Because of public health concerns, the agency disagrees that
phenolphthalein should remain on the market while further human safety
studies are being conducted and is stopping initial introduction or
initial delivery for introduction into interstate commerce of OTC
laxative drug products containing phenolphthalein as of the date this
final rule is published in the Federal Register.
4. Two manufacturers submitted comments (Refs. 2 through 8)
questioning the validity of the NTP data (Ref. 1). They argued that:
(1) The studies failed to demonstrate a proposed mechanism of genotoxic
action for phenolphthalein that is relevant to humans, (2) alternative
mechanisms were not considered, (3) the data obtained from the p53
deficient mouse study are inconsistent with what was expected based on
the 2-year carcinogenicity studies, (4) the NTP data do not provide a
sufficient basis for FDA to draw firm conclusions regarding the
potential human carcinogenicity of phenolphthalein, and (5) there are
no relevant human data to draw any firm conclusions regarding potential
risk of phenolphthalein in humans.
One comment submitted four consultant reports (Refs. 2 through 5),
which reanalyzed the NTP data. One report by Roe (Ref. 3) directed
criticisms primarily at the p53 deficient mouse study and the ``null''
mouse, which lacks both wild type p53 alleles. Roe dismissed the
positive genotoxicity results as apparent only under conditions of
toxicity or in some cases as an estrogenic effect. Roe also rejected
the findings of genotoxicity demonstrated for phenolphthalein in the
Chinese Hamster Ovary (CHO) cell chromosome aberrations assays, in the
several positive in vivo micronucleus assays, and in the mutation and
chromosomal aberration findings in the Syrian hamster embryo cells
(SHE) transformation assay by Tsutsui et al. (Ref. 9).
Two reports from CanTox U.S., Inc., (Refs. 2 and 4) concurred with
the estrogenic mechanism of carcinogenesis proposed by Roe. CanTox
proposed that an aneugenic effect may be involved and questioned the
validity of the mutagenicity data presented by Tsutsui et al. (Ref. 9)
for the SHE cell assay, noting that the control data were not different
from the treated groups.
One comment included a position paper on phenolphthalein from the
European Agency for the Evaluation of Medicinal Products, Committee for
Proprietary Medicinal Products (CPMP) (Ref. 7). The CPMP argued that
while carcinogenicity and genotoxicity for phenolphthalein were
confirmed by data from a transgenic mouse model, the systemic exposures
to active drug, both in the conventional rodent bioassays and p53
mouse, appeared to be well in excess of those likely to be encountered
in normal human use. CPMP stated that the extent of risk to humans
cannot be established without adequate mechanistic data addressing
whether a threshold exists for the carcinogenic
[[Page 4537]]
effects in mice and the in vivo genotoxic effects. CPMP added that it
was unable to verify from original data FDA's statement that the
``systemic exposures in rodents were approximately fortyfold to
seventyfold and sixtyfold to hundredfold the human exposure for rats
and mice, respectively.''
Another comment (Ref. 8) also reanalyzed the NTP data and
concluded that phenolphthalein was a genotoxic carcinogen in rodents.
No new information was submitted.
The comments did not submit any new data, but focused on
interpreting findings that already were available. The issue of
carcinogenicity through a genotoxic mechanism was discussed in the
proposed rule (62 FR 46223 at 46224) and at the April 30, 1997, FDA
Center for Drug Evaluation and Research (CDER) Carcinogenicity
Assessment Committee (CAC) meeting (Ref. 10). The CAC concluded that
the study in p53 heterozygous mice supports other evidence that
phenolphthalein may be carcinogenic through a genotoxic mechanism.
There was a clear dose-dependent increase in the incidence of thymic
lymphoma in the p53 assay, confirming one of the primary tumors of
concern to the CAC based on its original evaluation of the 2-year assay
data. These tumors occurred at doses that showed no other signs of
toxicity. Further, the CAC believed that the results of several of the
assays and data support a genotoxic clastogenic mechanism.
Phenolphthalein was positive in chromosome aberration tests and showed
chromosomal abnormality and hypoxanthine phosphoribosyltransferase
(hprt) mutations in the SHE cell assay, where nontoxic doses caused
cell transformation, mutations, and chromosome aberration. The p53
protein accumulation in the nucleus of thymic lymphoma cells of the
original 2-year mouse bioassay, coupled with the deletion of the wild
type p53 allele in the thymic lymphomas of p53 mice, is indicative of
interaction with the p53 gene as a target site. In vivo, repeated
exposure resulted in micronuclei in both the original bioassay and in
p53 mice studies. In the p53 mice, an increase in peripheral blood
micronucleus occurred even at the low doses (about 15 times the human
exposure) with increased duration of treatment without establishing a
no effect dose. Further, the exposures used to demonstrate these in
vivo and in vitro genotoxic effects were in the range that could occur
with human laxative use.
With regard to use of the p53 assay and its usefulness for
quantitative risk assessment, NTP used the p53 heterozygous mouse assay
to test phenolphthalein; therefore, many of the comments in Roe's
report regarding the ``null'' mouse (which lacks both wild type p53
alleles) do not apply. Information is available regarding the
responsiveness of the p53 model and the types of compounds to which it
responds. To date, when using a 6-month protocol design, the p53 mouse
only appears to respond to compounds known to be carcinogenic and
genotoxic, and not to compounds that are carcinogenic and nongenotoxic.
There is also no evidence to date that the p53 heterozygous mouse assay
that was used responds to carcinogens at significantly lower doses than
are positive in standard bioassays. Data for the micronucleus response
from Tice et al. (Ref. 11) indicate that, while the maximal response in
the p53 mouse is greater than for other strains of mice, response below
2,000 milligram/kilogram/day is similar to that of normal CD-1 mice
similarly treated with phenolphthalein. Furthermore, the tumor response
to phenolphthalein in the p53 model occurred over a dose range that
could have been predicted based on the results of the 2-year bioassay
in mice (assuming a genotoxic mechanism). Thus, the agency considers it
reasonable to use the p53 model as a part of the weight of evidence in
assessing a drug suspected of being a genotoxic carcinogen.
The agency further notes that the CAC's evaluation was not a
quantitative assessment for either the standard bioassays or the p53
assay, rather the data were viewed qualitatively considering exposure.
The evidence from several experimental studies indicating that
phenolphthalein acts through a genotoxic mechanism via deoxyribonucleic
acid (DNA) structural damage decreases the utility of a direct
quantitative risk assessment. The genotoxicity data were also
considered in the evaluation of the 2-year bioassay results, which
contributed significantly to the conclusion of a relevant risk to
humans. The p53 mouse assay was conducted under test conditions where
factors such as target organ toxicity did not confound its
interpretation, and where exposures and pharmacodynamic effects were
well characterized. Thus, the results of the p53 mouse assay appear to
be more likely relevant to humans than the results from the 2-year
bioassay as conducted.
Further, the agency disagrees with Roe's dismissal of the
genotoxic findings in the CHO cell chromosome aberration, micronucleus,
and SHE cell transformation assays as apparent under conditions of
toxicity or in some cases as an estrogenic effect. The agency is aware
that phenolphthalein is known to have estrogenic activity. The
information available on phenolphthalein indicates that its potency for
binding at estrogen receptors and for induction of estrogenic effects
is low compared to endogenous estrogens (by about a factor of
103 and 104 less than estradiol). Given the
concentrations of phenolphthalein achieved in the bioassays, this
action may be considered to have little overall contribution to the
estrogenic load in the rodent models tested. The types of tumors
observed for phenolphthalein are generally unlike those observed with
other estrogenic chemicals. While there may be some contribution by
estrogenic effects in the tumor response, the estrogenic effects appear
most relevant for the ovarian tumors observed only in the 2-year mouse
bioassay.
The genotoxic effects of phenolphthalein were observed under
conditions compatible with the International Conference on
Harmonization (ICH) guidance for the conduct of such genotoxicity
studies. Although the repeat dose micronucleus assay that was
originally reported was conducted at doses causing bone marrow
toxicity, which could be viewed as confounding the results, the
micronucleus assay conducted in the p53 mouse exhibited little evidence
of toxicity and yielded results essentially identical to those of the
prior assays. Thus, excessive toxicity is not essential to the
micronucleus response for phenolphthalein. Further, this assay,
although not part of the standard ICH test battery, is believed by many
in the scientific community to be a more comprehensive assessment than
the acute dose micronucleus assay, as it allows for any metabolic
induction processes that might occur in vivo. This assay also allows
exposures to achieve steady state conditions and reduces the
uncertainty of appropriate sampling times, which can confound the
standard acute assessments. Use of such tests is in accordance with ICH
recommended guidelines for additional genotoxicity testing where
positive findings have been observed in carcinogenicity studies.
The agency notes that there was an error in the Tsutui et al.
report (Ref. 9), in that the number of mutations found in the control
group for the SHE cell transformation assay should have been reported
as <0.25 x 10-6. The Tsutui et al. findings for the control
treatment are consistent with historical experience and less than 1/16
the response in phenolphthalein treated cells. The positive control
produced an effect only
[[Page 4538]]
threefold greater than phenolphthalein. Thus, these data indicate a
mutational effect for phenolphthalein.
The data also indicate that both aneuploidy and structural damage
are caused by phenolphthalein. Tice et al. (Ref. 11) showed a possible
increase in aneuploidy based on the kinetochore analysis. There was
also significant evidence of structural damage; phenolphthalein
treatment caused an approximate fourfold increase in micronuclei with
structural damage and an eightfold increase in aneugenic damage
calculated based on the ratio of normochromatic erythrocytes and
polychromatic erythrocytes, and the increase in micronuclei. Also, an
effect on aneuploidy was not observed in the study by Tsutsui et al.
(Ref. 9) with SHE cells, whereas DNA structural damage and mutation
were reported. The view that aneuploidy is the primary mechanism of
genetic damage related to the carcinogenic effect also ignores the
evidence of structural damage observed in the CHO cell chromosomal
aberration studies, including those done by NTP, with responses
approaching those seen with the positive control. Although the loss of
heterozygosity observed in tumors from the p53 mouse could be explained
by an aneugenic mechanism, it could also be the result of a chromosome
break or deletion of a significant segment of the p53 region targeted
by the assay. This allele loss was also specific for the p53 wild-type
gene, with no effect on the null allele. Such a selective effect would
not be anticipated from chromosome loss by an aneugenic mechanism
functioning at the spindle apparatus.
One CanTox report (Ref. 5) presented information on the effects of
phenolphthalein on thymidylate synthase (TS) activity and the potential
relationship to the genotoxic and carcinogenic effects observed
following phenolphthalein treatment in various systems. This report was
evaluated by FDA's Executive CAC and Genetic Toxicology Committees (the
Committees) (Ref. 12), which noted that the TS enzyme inhibitory
activity was reported for a bacterial source and could differ between
the bacterial and human or other mammalian forms, but there is no
information available for assessing increased or decreased sensitivity.
The Committees found no available information for estimation of
intracellular versus extracellular concentrations of phenolphthalein to
determine whether the in vivo phenolphthalein concentrations are within
a reasonable range of those that were studied in vitro for TS
inhibition. The inhibitor effects, however, appear to occur at plasma
concentrations of phenolphthalein tenfold to hundredfold greater than
the plasma concentrations associated with in vivo effects. There was
also no information available on the TS activity of the glucuronide or
other metabolites of phenolphthalein. In addition, the nucleotide pool
disruption model lacked in vivo data and other information showing that
a disruption of nucleotide pools was caused by phenolphthalein or that
nucleotide pool effects were involved in the observed responses to
phenolphthalein. The Committees noted that the effects of
phenolphthalein on induction of micronuclei could be considered
consistent with an effect on TS, based on comparisons of effects with
5-fluorouracil (5-FU) and methotrexate (MTX) treatment. However, the TS
inhibitory activity does not appear consistent with or explain the
other observed effects of phenolphthalein. In contrast to the assays
conducted on phenolphthalein, 5-FU and MTX failed to increase SHE cell
transformation. This suggests that, if phenolphthalein is active as a
TS inhibitor at the tested concentrations, its effects on SHE cells
(such as transformation, mutation, and chromosomal aberration) appear
independent of the TS activity. Also, phenolphthalein is associated
with increased chromosomal aberrations in CHO cells only in the
presence of metabolic activation. This contrasts with the ability of
phenolphthalein to directly inhibit TS. The comment's suggestion that
the effect in CHO cells is due to fragile site damage in the CHO cell
genome is not consistent with data provided by Witt et al. (Ref. 6),
nor with the observations on CHO cells discussed at the April 2, 1996,
CAC meeting (Ref. 13). In both data sets, there were increases in both
complex and simple chromosomal breaks. In the latter data set, the
proportionate response of simple and complex breaks appears similar to
that caused by cyclophosphamide (a known genotoxicant used as the
positive control for the assay). There was no discussion by the comment
as to why a fragile site response would not be relevant for human
adverse effects. The Committees noted that in a chromosomal aberration
assay on human peripheral blood lymphocytes tested in vitro (Ref. 14),
there was evidence of a clastogenic response from one of two subjects
tested. While there is evidence that phenolphthalein can inhibit TS in
some in vitro systems, the Committees stated that the data do not
support the argument that TS inhibition explains all of the genetic
damage observed in tests conducted on phenolphthalein, and that TS
inhibition is the underlying mechanism of tumor formation in the three
in vivo assays conducted. The Committees concluded that the data on TS
inhibition do not refute the potential relevance of phenolphthalein's
toxicologic effects for humans.
The CPMP (Ref. 7) contended that the extent of risk in humans
cannot be established because the mechanistic data are inadequate and
the phenolphthalein doses used in the study were excessive. The agency
is not aware of any available data that would suggest that the
mechanisms thought to account for tumor induction by phenolphthalein in
experimental animals would not also operate in humans. Further, the
phenolphthalein exposures used to demonstrate the in vivo and vitro
genotoxic effects were in the range of those that humans use to cause
laxation. The agency also notes that the exposure information for
phenolphthalein that the CPMP could not verify was based on data
obtained from a kinetic study (Ref. 15) sponsored by the 1992-1993
Nonprescription Drug Manufacturers Association Phenolphthalein Study
Group.
After review of all the available data, the agency concludes that
phenolphthalein caused chromosome aberrations, cell transformation, and
mutagenicity in mammalian cells. Because benign and malignant tumor
formation occurs at multiple tissue sites in multiple species of
experimental animals, phenolphthalein is reasonably anticipated to have
human carcinogenic potential.
III. References
1. Comment No. RPT7, Docket No. 78N-036L, Dockets Management
Branch.
2. CanTox U.S., Inc., ``Discussion of New Data Related to
Phenolphthalein Presented at the April 30, 1997 Meeting of the
Carcinogenicity Assessment Committee of the U.S. Food and Drug
Administration,'' June 9, 1997, in Comment No. C167, Docket No. 78N-
036L, Dockets Management Branch.
3. Roe, F. J., ``Opinion on the Safety of Phenolphthalein as an
Ingredient of OTC Laxative Preparations,'' August 28, 1996, in
Comment No. C180, Docket No. 78N-036L, Dockets Management Branch.
4. CanTox U.S., Inc., ``Evaluation of the Rodent
Carcinogenicity of Phenolphthalein,'' October 1, 1997, in Comment
No. C180, Docket No. 78N-036L, Dockets Management Branch.
5. CanTox U.S., Inc., ``The Relevance of the Role of
Phenolphthalein as an Inhibitor of Thymidylate Synthase for the
Interpretation of the Genotoxic Potential and Carcinogenicity
Assessment of this Compound,'' December 4, 1997, in Comment No.
C186, Docket No. 78N-036L, Dockets Management Branch.
[[Page 4539]]
6. Witt, K. L. et al., ``Phenolphthalein: Induction of
Micronucleated Erythrocytes in Mice,'' Mutation Research, 341:151-
160, 1995, in Comment No. C186, Docket No. 78N-036L, Dockets
Management Branch.
7. Comment No. C189, Docket No. 78N-036L, Dockets Management
Branch.
8. Comment No. RPT9, Docket No. 78N-036L, Dockets Management
Branch.
9. Tsutsui, T. et al., ``Cell Transforming Activity and
Genotoxicity of Phenolphthalein in Cultured Syrian Hamster Embryo
Cells,'' unpublished manuscript, 1997, in Comment No. RPT7, Docket
No. 78N-036L, Dockets Management Branch.
10. Comment No. MM13, Docket No. 78N-036L, Dockets Management
Branch.
11. Tice, R. R. et al., ``Tumorigenicity Studies of Dietary
Phenolphthalein (CAS No. 77-09-8) in TSG-p53 Transgenic Female
Mice,'' final report, April 11, 1997, in Comment No. RPT7, Docket
No. 78N-036L, Dockets Management Branch.
12. Comment No. MM15, Docket No. 78N-036L, Dockets Management
Branch.
13. Comment No. MM12, Docket No. 78N-036L, Dockets Management
Branch.
14. Comment No. RPT10, Docket No. 78N-036L, Dockets Management
Branch.
15. BTC Study No. P0392002 in Comment No. RPT11, Docket No.
78N-036L, Dockets Management Branch.
5. One comment expressed concern about the availability of an
acceptable bowel cleansing system for use by physicians if the use of
phenolphthalein is banned. The comment argued that its bowel cleansing
system containing phenolphthalein, magnesium citrate, and bisacodyl
should not be considered an OTC laxative. The comment stated that if
phenolphthalein cannot be used, patients may be misdiagnosed because
adequate bowel cleansing was not achieved prior to undergoing a bowel
examination. The comment requested that the agency allow the continued
sale of phenolphthalein in bowel cleansing systems if the product is
adequately labeled, limited to a one-time application, and purchased
and used under a physician's supervision.
This final rule prohibits the use of phenolphthalein in OTC
laxative drug products. If an OTC bowel cleansing system is
reformulated to contain a different laxative ingredient, data must be
submitted to the rulemaking for OTC laxative ingredients to support the
safety and effectiveness of the reformulated bowel cleansing system.
Bowel cleansing systems that contain phenolphthalein and are limited to
purchase and use under a physician's supervision may be submitted for
agency review in a new drug application.
6. One comment stated that if phenolphthalein is reclassified as a
Category II ingredient in the final rule, an immediate effective date
would be unfair because it would cause significant economic harm to
manufacturers of phenolphthalein. The comment recommended that a 1-year
transition period be allowed for manufacturers to reformulate their
laxative products, which will involve the purchase and production of
new materials and, possibly, new equipment. The comment did not present
any information that was not previously addressed in the proposed rule.
Because over 1 year has passed since the proposal was published,
providing adequate time for reformulation, the agency denies the
comment's request. In the preamble to the proposed rule (58 FR at 46226
to 46227), FDA found good cause under 5 U.S.C. 553(d) and 21 CFR
10.40(c)(4) for an immediate effective date for this final rule. In the
reasons given in that preamble, as well as the fact that an additional
period of more than 1 year has passed; the agency confirms the finding
of good cause for an immediate effective date for this final rule.
IV. The Agency's Final Conclusions on Danthron and Phenolphthalein
Based on new data and information, the agency is reclassifying the
stimulant laxative ingredients danthron and phenolphthalein from
Category I (monograph) to Category II (nonmonograph) and is adding
danthron and phenolphthalein to the list of stimulant laxatives in
Sec. 310.545(a)(12)(iv). The current list in that section is
redesignated as Sec. 310.545(a)(12)(iv)(A) and danthron and
phenolphthalein are being included in new Sec. 310.545(a)(12)(iv)(B).
As a result of this reclassification of danthron and phenolphthalein,
the amendments proposed in Secs. 334.18, 334.30, 334.32, 334.60, and
344.66 (62 FR 46223 at 46227) will be finalized in the final rule for
OTC laxative drug products, to be published in a future issue of the
Federal Register.
V. Analysis of Impacts
One comment was received in response to the agency's request in
the proposal for specific comment on the economic impact of this
rulemaking (62 FR 46223 at 46225). (See comment 6 of this document.)
FDA has examined the impacts of this final 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 final rule is consistent with the
principles set out in the Executive Order and in these two statutes.
The purpose of this final rule is to establish conditions under which
the OTC stimulant laxative ingredients danthron and phenolphthalein are
not generally recognized as safe and effective. Cessation of marketing
of OTC laxative drug products containing danthron occurred in 1987.
Therefore, no reformulation or relabeling will be necessary for this
ingredient.
Products containing phenolphthalein will need to be reformulated
to replace the ingredient with another laxative active ingredient. A
number of laxative ingredients in proposed part 334 (50 FR 2124 at
2152) could be used. In addition, most OTC laxative drug products
containing phenolphthalein have already been reformulated since the
proposal was published.
When the proposed rule was published, the agency was aware of only
one phenolphthalein dosage form, a flavored chewable tablet. Sales of
this dosage form by all manufacturers were about $20 million in 1995
(most attributed to one large manufacturer), comprising about 3 percent
of the total retail market for laxative products. The major
manufacturer of this product informed the agency on August 29, 1997 (
Ref. 1), that it planned to reformulate the product with another OTC
laxative ingredient within 60 days.
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
[[Page 4540]]
that duplicate, overlap, or conflict with this rule.
Based on the agency's understanding that most manufacturers have
already reformulated or otherwise are in the process of reformulating,
the agency expects that this final 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
Reform Act). The agency also believes that it has undertaken steps to
reduce the burden to small entities. Nevertheless, some entities may
incur significant impacts, especially manufacturers that still must
reformulate their phenolphthalein products and, to a lesser extent,
private label manufacturers that provide labeling for a number of the
affected products. Danthron was removed from OTC laxative drug products
in 1987 and has not been available for approximately 10 years.
Therefore, it is unlikely that reclassification of danthron as a
nonmonograph ingredient would have any economic impact. 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.
VI. Reference
1. Comment No. C173, Docket No. 78N-036L, Dockets Management
Branch.
VII. 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.
VIII. Environmental Impact
The agency has determined under 21 CFR 25.31(c) 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.
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:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.
2. Section 310.545 is amended by redesignating paragraph
(a)(12)(iv) as paragraph (a)(12)(iv)(A) and by revising the newly
redesignated heading, by adding paragraphs (a)(12)(iv)(B) and (d)(29),
and by revising paragraph (d) introductory text and paragraph (d)(1) to
read as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(12) * * *
(iv)(A) Stimulant laxatives--Approved as of May 7, 1991. * * *
(iv)(B) Stimulant laxatives--Approved as of January 29, 1999.
Danthron
Phenolphthalein
* * * * *
(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)(29) of this section.
(1) May 7, 1991, for products subject to paragraphs (a)(1) through
(a)(2)(i), (a)(3) through (a)(4), (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) through (a)(12)(iv)(A),
(a)(14) through (a)(15)(i), and (a)(16) through (a)(18) of this
section.
* * * * *
(29) January 29, 1999, for products subject to paragraph
(a)(12)(iv)(B) of this section.
Dated: January 20, 1999.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 99-1938 Filed 1-28-99; 8:45 am]
BILLING CODE 4160-01-F