[Federal Register Volume 60, Number 33 (Friday, February 17, 1995)]
[Proposed Rules]
[Pages 9554-9558]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4007]



    [[Page 9528]]   

[[Page 9553]]

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Part VII





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 201



Topical Drug Products Containing Benzoyl Peroxide; Required Labeling; 
Proposed Rule

Federal Register / Vol. 60, No. 33 / Friday, February 17, 1995 / 
Proposed Rules
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[[Page 9554]] 


DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
21 CFR Part 201

[Docket No. 92N-0311]


Topical Drug Products Containing Benzoyl Peroxide; Required 
Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing additional 
labeling (warning and directions) for all topically-applied acne 
treatment drug products containing benzoyl peroxide. The warning 
advises consumers to avoid unnecessary sun exposure and to use a 
sunscreen when using a benzoyl peroxide product to treat acne. The 
directions provide information about applying benzoyl peroxide and a 
sunscreen, and about discontinuing use of both products if irritation 
or sensitivity develops. Prescription drug products will need a patient 
package insert to convey this information to product users. The agency 
is requesting public comment on whether a consumer package insert 
should be required to provide additional information FDA believes users 
of these benzoyl peroxide products should have. That information would 
summarize some problems that occurred when benzoyl peroxide was used in 
tests on mice and would mention that additional studies are currently 
being conducted. The final status of benzoyl peroxide in over-the-
counter (OTC) drug products and the continued need for the additional 
labeling will be determined when these additional studies are completed 
and evaluated.

DATES: Written comments on the proposed regulation by May 18, 1995. 
Written comments on the agency's economic impact determination by May 
18, 1995. FDA is proposing that the final rule based on this proposal 
be effective 6 months after the date of its publication in the Federal 
Register.

ADDRESSES:  Written comments to the Dockets Management Branch (HFA-
305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:  William E. Gilbertson, Center for 
Drug Evaluation and Research (HFD-810), Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: In the Federal Register of August 7, 1991 
(56 FR 37622), FDA published, under Sec. 330.10(a)(6) (21 CFR 
330.10(a)(6)), an amendment of the tentative final monograph for 
topical acne drug products for OTC human use in which the agency 
reclassified benzoyl peroxide from its previously proposed monograph 
status (Category I) to ``more-data-needed'' (Category III) status. This 
action (56 FR 37622) was based on new information that raised a safety 
concern regarding benzoyl peroxide as a tumor promoter in mice (Ref. 1) 
and a study that reported that benzoyl peroxide has tumor initiation 
potential (Ref. 2).
    Subsequently, a drug manufacturers association submitted data and 
information in support of the safety of benzoyl peroxide (Refs. 3 
through 6). FDA evaluated these data and information and determined 
that the studies show that benzoyl peroxide is a skin tumor promoter in 
more than one strain of mice as well as in hamsters. To date, topical 
studies (which have shown only tumor promotion) have been of short 
duration (about 52 weeks). Although animal data and human epidemiology 
data are available, the agency has determined that further studies are 
necessary to adequately assess the tumorigenic potential of benzoyl 
peroxide. These studies are currently being conducted (Ref. 7). The 
agency acknowledges that it may take several years for these studies to 
be completed and analyzed, and for a final determination to be made on 
benzoyl peroxide's safety.
    Because studies have shown that benzoyl peroxide is a skin tumor 
promoter in animals, and the relevance of this finding to humans is 
unknown, the agency was concerned about continued OTC marketing during 
the several years it will take to resolve the safety issues raised by 
the studies discussed above. Because of this concern, the agency 
discussed this matter with its Dermatologic Drugs Advisory Committee 
(the Committee) on April 10, 1992 (Ref. 8). At that meeting, 
information was presented by representatives of FDA and industry, 
consumer, and professional organizations. The Committee was asked to 
assess the safety and efficacy data available for benzoyl peroxide, to 
consider the benefit-to-risk ratio, and to recommend whether the 
product should continue to be available for use while further safety 
data are developed. The Committee voted unanimously that benzoyl 
peroxide should remain available as an OTC drug product.
    The Committee was also asked whether the OTC labeling of benzoyl 
peroxide drug products should be changed to include a statement 
concerning the ingredient's potential to cause skin tumors in animals, 
what is the relevance of this potential in humans, and how such a 
statement should be worded for consumers. The Committee recommended by 
a four to three vote (with one abstention) that information about what 
is known about benzoyl peroxide should be provided to consumers by some 
mechanism. Because of the lack of data, however, the Committee 
recommended that no warning statement concerning cancer should be 
included in the labeling of benzoyl peroxide products. The Committee 
recommended unanimously that FDA consider appropriate wording for 
additional labeling to highlight those areas where there may be risks 
and that the proposed wording be brought back to the Committee for 
review.
    The Committee was also informed that the agency had previously 
recommended to industry that a lifetime animal carcinogenicity study to 
assess benzoyl peroxide's safety include, as part of the protocol, 
periods of exposure to UV light (Ref. 9). The Committee was asked its 
opinion on the need for such testing. Industry representatives stated 
to the Committee that studies already conducted by Iversen (Refs. 10 
and 11) showed no evidence that benzoyl peroxide enhanced the 
carcinogenicity of UV light. After a lengthy discussion, the Committee 
concluded that the Iversen studies were insufficient to fully resolve 
this issue because they were not animal lifetime studies and an 
insufficient number of animals had been used. Further, based on the 
protocol, it was uncertain that the studies provided assurance that 
benzoyl peroxide's tumor fostering potential was conclusively assessed. 
The Committee recommended unanimously that a new photocarcinogenicity 
study should be conducted (Ref. 12). As noted above, this study is 
being conducted (Ref. 7).
    A comment submitted after the Committee meeting (Ref. 13) from a 
consumer association urged the agency to move quickly to inform the 
American public of the possible health and safety risks associated with 
benzoyl peroxide. The comment did not recommend removal of this drug 
from the OTC market, but suggested several labeling statements that 
could be used. Another comment by a national manufacturers association 
(Ref. 14) suggested that FDA use alternative available methods, rather 
than labeling, to disseminate information on this subject. The 
association proposed: (1) Fact Sheets mailed to consumer groups and 
publishers of medical- and pharmacy- [[Page 9555]] related information, 
(2) publications in FDA Consumer, and (3) other similar and related 
mechanisms. The association stated that the OTC label should be 
maintained as an instructional tool for safe product use rather than 
for the dissemination of ambiguous, potentially frightening information 
that the consumer has little ability to make an informed decision 
about.
    The association contended that labeling already proposed by the 
agency for benzoyl peroxide pertaining to ``skin irritation'' (50 FR 
2172 at 2181, January 15, 1985) would take into account the 
hypothetical mechanism of skin tumor promotion which--although not 
known to occur in humans--represents the best model to date to describe 
the possible risk that is at issue with benzoyl peroxide. The comment 
concluded that the proposed warning conforms to the Committee's 
recommendations, i.e., avoids the term ``cancer'' yet provides 
information to the public, is instructional and actionable, and allows 
consumers to take definitive risk avoidance action by not using the 
product.
    The agency has carefully considered the Committee's and the 
comments' views. The agency agrees that marketing of benzoyl peroxide 
should continue while the ongoing studies are being completed. The 
agency agrees that information should be provided to consumers and that 
no warning statement concerning cancer should be included in the 
labeling of benzoyl peroxide drug products because currently available 
data are inconclusive. The agency has given extensive consideration to 
the potential risks established to date, e.g., sun exposure, and is 
proposing certain labeling information that it believes should be 
provided to consumers now. The bases for these proposals follow.
    Although the skin tumor promotion caused by benzoyl peroxide in 
mice and hamsters is disturbing, the overall test results are not 
conclusive, and the risk to humans is unknown. In recent epidemiologic 
studies (Refs. 15 and 16), Hogan et al. concluded that there is no 
indication that the normal use of benzoyl peroxide in the treatment of 
acne is associated with an increased risk of acial skin cancer.
    Benzoyl peroxide is a widely used and effective ingredient in the 
topical treatment of acne. As noted above, the Committee recommended 
unanimously that benzoyl peroxide should remain available as an OTC 
drug product while the additional studies to answer the unresolved 
safety questions are being conducted. When those studies are completed, 
the monograph or nonmonograph status of benzoyl peroxide will be 
resolved.
    FDA has determined that the results of available animal studies do 
not provide a sufficient basis to restrict OTC marketing of benzoyl 
peroxide products at this time. However, the agency has tentatively 
determined that consumers who choose to use products containing this 
ingredient need to be informed about an additional condition related to 
this use, i.e., to avoid unnecessary sun exposure and to use a 
sunscreen. The agency has also determined that it would be desirable to 
provide users of benzoyl peroxide products some additional information 
about this drug based on the studies that have been and are being 
conducted.
    The agency has considered the comments' viewpoints on how consumers 
should be informed about this new information and finds that the 
various suggestions have merit. The agency tentatively finds that the 
best way to directly inform users of benzoyl peroxide drug products 
about sun exposure and this ingredient is to provide the information in 
product labeling. The agency will also disseminate this information in 
other standard ways, e.g., the FDA Consumer and the FDA Medical 
Bulletin. The agency will be able to provide more detailed information 
in these publications than can be provided in OTC drug product 
labeling.
    Based on the above discussion, the agency is proposing to require 
that the labeling of products containing benzoyl peroxide include a new 
warning and additional directions. The warning advises users of these 
products to avoid unnecessary sun exposure and to use a sunscreen. The 
agency believes that the warning information is important enough that 
it should appear in boldface type as the first statement under the 
heading ``WARNINGS.'' The additional directions provide information 
about applying the benzoyl peroxide and sunscreen. For OTC drug 
products containing benzoyl peroxide, the agency is proposing that the 
following information be used:
    (1) The following statement shall appear in boldface type as the 
first sentence under the heading ``Warnings'': ``When using this 
product, avoid unnecessary sun exposure and use a sunscreen.''
    (2) The following information shall appear in the ``Directions'' 
section of the labeling: ``If going outside, use a sunscreen. (sentence 
in boldface type) Allow [insert name of benzoyl peroxide product] to 
dry, then follow directions in the sunscreen labeling. If irritation or 
sensitivity develops, discontinue use of both products and consult a 
doctor.''
    Prescription drug products will need a patient package insert to 
convey this information to users of the product. For prescription drug 
products, the agency is proposing that this same information appear in 
a patient package insert in accord with 21 CFR 201.57(f)(2) and new 
Sec. 201.318 (21 CFR 201.318) of this chapter, which is being proposed 
in this document.
    The agency would like public comment on how beneficial it would be 
to provide users of OTC and prescription drug products containing 
benzoyl peroxide additional information on what is known about the 
ingredient. This information would summarize in lay language some 
problems that occurred when benzoyl peroxide was used in tests in mice 
and would inform users of the product that additional studies are 
currently being conducted. The information would also state that 
consumers can continue to use benzoyl peroxide products while these 
tests are being done. The agency is contemplating requiring this 
information to appear in a consumer package insert because it is too 
extensive to appear on the immediate container or carton labeling. If 
implemented, the requirement would appear as follows:
    The following information shall appear in a package insert under 
the heading ``Additional Information About'' (insert brand name of 
benzoyl peroxide product):
    What is in (insert brand name of benzoyl peroxide product)?
    The main active ingredient in (insert brand name of product) is 
benzoyl peroxide. People have used it for more than 25 years to 
treat pimples and acne. In animal tests, benzoyl peroxide was put on 
the skin of mice after other chemicals known to cause tumors. 
Benzoyl peroxide appeared to make the tumors caused by the other 
chemicals grow faster, but benzoyl peroxide did not cause tumors by 
itself. Substances that cause tumors to grow or to grow faster in 
animals raise questions about the possibility of a similar effect in 
humans. However, many such substances have had no effect on human 
tumors.
    Does Benzoyl Peroxide Cause Tumors to Grow in Humans?
    A Canadian survey looked at people who did and did not use 
benzoyl peroxide. The people who used benzoyl peroxide did not have 
any more skin tumors than those who did not use it.
    No one study can answer all the important questions about the 
effects of a medicine. This Canadian survey did not consider the 
effects of using benzoyl peroxide for many years or in places where 
people may be exposed to other causes of skin tumors, such as 
locations that get more sunlight. More studies are being done now.
     What Should I Do? [[Page 9556]] 
    At this time, a group of doctors called together by the Food and 
Drug Administration believe it is okay to continue to use benzoyl 
peroxide to help clear up pimples while more studies are being done. 
There is no evidence that the drug causes tumors or causes tumors to 
grow faster in humans.
    If you decide to use this medicine, you should try to avoid 
possible causes of tumors. Because sunlight can cause tumors in 
humans, you should stay out of sunlight as much as possible and use 
a sunscreen when you go outside.
    This leaflet will be revised when more is known about the 
effects of benzoyl peroxide.
    This labeling would apply equally to both OTC and rescription drug 
products that contain benzoyl peroxide. At this time, only one 
prescription product (a combination product containing benzoyl peroxide 
and erythromycin) is subject to an approved application. Other 
prescription products are currently marketed without approved 
applications. This labeling would apply to any prescription product 
containing benzoyl peroxide, whether marketed under or without an 
approved application.
    The agency is especially concerned whether the benzoyl peroxide 
warning will be read and understood by teenagers, the largest group of 
targeted consumers of acne drug products, and, if read, if they will 
comply with the warning. An additional concern is the possibility that 
the proposed labeling may result in teenagers not treating acne at all, 
although dermatologists consider this an abnormal skin condition that 
should be treated. Based on these concerns, the agency invites public 
comment, particularly with supporting information, regarding label 
reading, label understanding, and making use of the information, 
especially with regard to the teenage population. The agency also 
invites comment on whether the proposed consumer package insert would 
provide useful information to teenagers. An alternative to the labeling 
approach that FDA is proposing would be to place the ingredient on 
prescription status until the testing is completed. At that time, the 
skin tumor promotion issue and the effects of sun exposure should be 
resolved, and a final decision can be made on the monograph or 
nonmonograph status of this ingredient.
    Based on all information currently available, the agency considers 
the known benefits of the OTC availability of products containing 
benzoyl peroxide to exceed the possible safety risks. However, until a 
final determination is made on the OTC status of benzoyl peroxide, the 
agency tentatively concludes that additional information about the 
ingredient needs to be provided to consumers. The agency considers the 
labeling being proposed in this document to be in accord with the 
provisions of sections 201(n) and 502(a) of the act (21 U.S.C. 321(n) 
and 352(a)).
    The agency acknowledges that there currently is a lack of 
information on possible interactions between products containing 
benzoyl peroxide and products containing a sunscreen (or sunscreens). 
There are numerous benzoyl peroxide products in the marketplace, and 
these products are formulated with a variety of inactive ingredients. 
Likewise, there are many sunscreens in the marketplace, and these 
products are formulated with a variety of inactive ingredients, which 
in some cases are different than those contained in the benzoyl 
peroxide products. However, the agency is unable to state whether any 
incompatibilities may occur when the two types of products are used 
sequentially. The agency believes that users should allow the benzoyl 
peroxide to dry before applying the sunscreen. This would not be a 
concern if the benzoyl peroxide is applied at bed time and the 
sunscreen is applied the following morning. However, some users will 
reapply the benzoyl peroxide in the morning before going outside. 
Sunscreen applied soon after the benzoyl peroxide could interact with 
the benzoyl peroxide product. Therefore, the agency is considering the 
following product labeling to inform consumers: ``There currently is a 
lack of information on possible interactions between products 
containing benzoyl peroxide and products containing a sunscreen (or 
sunscreens).''
    The agency is aware that the prescription ingredient tretinoin, 
which is used for the topical treatment of acne, states in its labeling 
(Ref. 17) that ``Use of sunscreen products and protective clothing over 
treated areas is recommended when exposure [to sunlight] cannot be 
avoided.'' However, the labeling does not provide any directions about 
the time or method of applying he sunscreen. The same manufacturer also 
markets benzoyl peroxide acne drug products. Thus, the manufacturer may 
have information in its files about the use of a sunscreen following 
topical acne drug products containing benzoyl peroxide. Manufacturers 
of both benzoyl peroxide and sunscreen products are invited to comment 
on the appropriateness of a waiting period between application of the 
two products and to submit any information available in their files on 
sequential use of these types of products.
    Because the agency is encouraging manufacturers of benzoyl peroxide 
products to voluntarily implement the labeling in this proposal as soon 
as possible (see discussion below), manufacturers may wish or need to 
add additional information in their labeling about application 
intervals as appropriate for their specific product.

References

    (1) Slaga, T. J. et al., ``Skin-Tumor Activity of Benzoyl 
Peroxide, A Widely Used Free Radical-Generating Compound,'' Science, 
213:1023-1025, 1981.
    (2) Kurokawa, Y. et al., ``Studies on the Promoting and Complete 
Carcinogenic Activities of Some Oxidizing Chemicals in Skin 
Carcinogenesis,'' Cancer Letters, 24:299-304, 1984.
    (3) Comment No. RPT, Docket No. 81N-0114, Dockets Management 
Branch.
    (4) Comment No. RPT 00002, Docket No. 81N-0114, Dockets 
Management Branch.
    (5) Comment No. SUP00002, Docket No. 81N-0114, Dockets 
Management Branch.
    (6) Comment No. SUP00003, Docket No. 81N-0114, Dockets 
Management Branch.
    (7) Comments No. C31, PR1, and PR2, Docket No. 81N-0114, Dockets 
Management Branch.
    (8) Transcript of 34th meeting of FDA's Dermatologic Drugs 
Advisory Committee, April 10, 1992, Bethesda, MD, pp. 10-22, 112-
117, 146-149, 177-184, 234-236, and 262-266, OTC vol. No. 07BP, 
Docket No. 92N-0311, Dockets Management Branch.
    (9) Comment No. MM4, Docket No. 81N-0114, Dockets Management 
Branch.
    (10) Iversen, O. H., ``Carcinogenesis Studies with Benzoyl 
Peroxide (Panoxyl gel 5%),'' Journal of Investigative Dermatology, 
86:442-448, 1986.
    (11) Iversen, O. H., ``Skin tumorigenesis and carcinogenesis 
studies with 7, 12-dimethylbenz [a] anthracene, ultraviolet light, 
benzoyl peroxide (Panoxyl gel 5%) and ointment gel,'' 
Carcinogenesis, 9:803-809, 1988.
    (12) Transcript of 34th meeting of FDA's Dermatologic Drugs 
Advisory Committee, April 10, 1992, Bethesda, MD, pp. 277-279, OTC 
vol. No. 07BP, Docket No. 92N-0311, Dockets Management Branch.
    (13) Comment No. C6, Docket No. 81N-114A, Dockets Management 
Branch.
    (14) Comment No. C7, Docket No. 81N-114A, Dockets Management 
Branch.
    (15) Hogan, D. J., T. To, and E. R. Wilson, ``Drug and Non-Drug 
Risk Factors Associated With Facial Skin Cancer,'' A report to the 
Nonprescription Drug Manufacturers Association/the Nonprescription 
Drug Manufacturers Association of Canada on the Saskatchewan Study, 
Comment No. 4, Docket No. 81N-114A, Dockets Management Branch.
    (16) Hogan, D. J. et al., ``A Study of Acne treatments as Risk 
Factors for Skin Cancer of the Head and Neck,'' British Journal of 
Dermatology, 125(4):343-348, 1991.
    (17) ``Physicians Desk Reference--1993,'' 47 ed., Medical 
Economics Co., Montvale, NJ, pp. 1736-1737, 1993.
    Manufacturers of all drug products containing benzoyl peroxide are 
[[Page 9557]] encouraged to voluntarily implement this labeling as of 
the date of publication of this proposal, subject to the possibility 
that FDA may change the wording of the statement, or not require the 
statement, as a result of comments filed in response to this proposal. 
Because FDA is encouraging that the proposed labeling statement be used 
on a voluntary basis at this time the agency advises that manufacturers 
will be given ample time after publication of a final rule to use up 
any labeling implemented in conformance with this proposal.
    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
Order and, thus, is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The proposed rule is estimated to generate a one-
time label modification, the cost of which will not be significant. 
Similarly, the costs incurred by small businesses are estimated to be 
insufficient to warrant a regulatory flexibility analysis. FDA believes 
that small marketers use relatively simple and inexpensive packaging 
and labeling. Hence, labeling change costs to small firms are not 
expected to be substantial. Accordingly, the agency certifies that the 
proposed rule will not have a significant economic impact on a 
substantial number of small entities. Therefore, under the Regulatory 
Flexibility Act, no further analysis is required.
    The agency invites public comment regarding any substantial or 
significant economic impact that this rulemaking would have on 
manufacturers of drug products that contain benzoyl peroxide. Comments 
regarding the impact of this rulemaking on benzoyl peroxide containing 
drug products should be accompanied by appropriate documentation. A 
period of 90 days from the date of pubication of this proposed 
rulemaking in the Federal Register will be provided for comments on 
this subject to be developed and submitted. 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.
    The agency has determined under 21 CFR 25.24(c)(6) 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.
    Interested persons may, on or before May 18, 1995, submit written 
comments to the Dockets Management Branch (address above). Written 
comments on the agency's economic impact determination may be submitted 
on or before May 18, 1995. 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. Comments may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.
    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 part 201 be amended as follows:

PART 201--LABELING

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

    Authority:  Secs. 201, 301, 501, 502, 503, 505, 506, 507,508, 
510, 512, 530-542, 701, 704, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 358, 
360, 360b, 360gg-360ss, 371, 374, 379e); secs. 215, 301, 351, 361 of 
the Public Health Service Act (42 U.S.C. 216, 241, 262, 264).

    2. New Sec. 201.318 is added to subpart G to read as follows:


Sec. 201.318  Labeling for benzoyl peroxide-containing topical 
preparations; required statements.

    (a) Studies have shown that skin tumors were fostered in laboratory 
animals exposed to benzoyl peroxide and tumor initiators. It is also 
known that excessive sunlight can cause skin cancer in humans. Animal 
studies are in progress to investigate whether benzoyl peroxide is a 
tumor promoter or initiator in the absence and/or presence of sunlight. 
While these studies are being conducted, and until the results of the 
studies have been assessed, FDA concludes that the labeling of topical 
drug products containing benzoyl peroxide should inform users of the 
product that some harm may result from exposure to sunlight in 
conjunction with the use of products containing benzoyl peroxide. 
Accordingly, a warning and additional directions must appear in the 
labeling of prescription or over-the-counter (OTC) drug products that 
contain benzoyl peroxide.
    (b) Any OTC drug product containing benzoyl peroxide for topical 
administration shall bear the following statement in its labeling:
    (1) The following statement shall appear in boldface type as the 
first sentence under the heading ``Warnings'': ``When using this 
product, avoid unnecessary sun exposure and use a sunscreen.''
    (2) The following information shall appear in the ``Directions'' 
section of the labeling: ``If going outside, use a sunscreen. (sentence 
in boldface type) Allow [insert name of benzoyl peroxide product] to 
dry, then follow directions in the sunscreen labeling. If irritation or 
sensitivity develops, discontinue use of both products and consult a 
doctor.''
    (c) Requirement for a patient package insert for any prescription 
drug product containing benzoyl peroxide for topical administration. 
Each topical benzoyl peroxide product restricted to prescription 
distribution, including any benzoyl peroxide in fixed combination with 
other drugs, shall be dispensed to patients with a patient package 
insert containing the information in paragraph (c)(2)(iii) of this 
section. This requirement applies to any topical benzoyl peroxide drug 
product that is the subject of a new drug application approved either 
before or after October 9, 1962, and all identical, related, or similar 
drug products as defined in Sec. 310.6 of this chapter, whether or not 
the subject of an approved new drug application.
    (1)  Distribution requirements. For topical benzoyl peroxide drug 
products, the manufacturer and distributor shall provide a patient 
package insert in or with each package of the drug product that the 
manufacturer or distributor intends to be dispensed to a patient. The 
patient labeling shall be provided as a separate printed leaflet 
independent of any additional materials provided with the product.
    (2) Patient package insert contents. A patient package insert for a 
topical benzoyl peroxide drug product is required to contain the 
following information:
    (i) The name of the drug. [[Page 9558]] 
    (ii) The name and place of business of the manufacturer, packer, or 
distributor.
    (iii) The following statement: WARNING: ``When using this product, 
avoid unnecessary sun exposure and use a sunscreen.'' (sentence and 
word WARNING in boldface type)
    (iv) The following information shall appear in the ``Directions'' 
section of the labeling: ``If going outside, use a sunscreen. (sentence 
in boldface type) Allow [insert name of benzoyl peroxide product] to 
dry, then follow directions in the sunscreen labeling. If irritation or 
sensitivity develops, discontinue use of both products and consult a 
doctor.''
    (v) The date, identified as such, of the most recent revision of 
the patient package insert.
    (3)  Requirements to supplement approved application. Holders of 
approved applications for topical benzoyl peroxide drug products that 
are subject to the requirements of this section must submit supplements 
under Sec. 314.70(c) of this chapter to provide for the labeling 
required by paragraph (c) of this section. Such labeling may be put 
into use without advance approval of the Food and Drug Administration 
provided it includes only the information included in paragraph(c) of 
this section.
    (d) Any drug product subject to this section that is not labeled as 
required and that is initially introduced or initially delivered for 
introduction into interstate commerce after (insert date 6 months after 
date of publication of the final rule in the Federal Register) is 
misbranded under section 502 of the Federal Food, Drug, and Cosmetic 
Act and is subject to regulatory action.

    Dated: January 31, 1995.
William K. Hubbard,
Interim Deputy Commissioner for Policy.
[FR Doc. 95-4007 Filed 2-16-95; 8:45 am]
BILLING CODE 4160-01-F