Topical Drug Products Containing Benzoyl Peroxide; Required Labeling

Federal RegisterFeb 17, 1995

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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

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: