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

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.

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

§ 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 ‘‘moredata-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-
Federal Register / Vol. 60, No. 33 / Friday, February 17, 1995 / Proposed Rules 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 § 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?
9556 Federal Register / Vol. 60, No. 33 / Friday, February 17, 1995 / Proposed Rules

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