Federal Register / Vol. 66, No. 103 / Tuesday, May 29, 2001 / Proposed Rules 29059

notice number of this NPRM. Persons

interested in being placed on a mailing

list for future NPRMs should also

request a copy of Advisory Circular No.

11–2A, which describes the application

procedure.

The Proposal

The FAA is considering an

amendment to Part 71 of the Federal

Aviaiton Regulations (14 CFR part 71) to

establish Class E airspace area at

Couldersport, PA. An RNAV Approach,

Helicopter RNAV 343, has been

developed for Charles Cole Memorial

Hospital Heliport, Couldersport, PA.

Controlled airspace extending upward

from 700 feet AGL is needed to

accommodate the SIAP. Class E airspace

designations for airspace areas

extending upward from 700 feet from or

above the surface are published in

Paragraph 6005 of FAA Order 7400.9H,

dated September 1, 2000, and effective

September 16, 2000, which is

incorporated by reference in 14 CFR

71.1. The Class E airspace designation

listed in this document would be

published subsequently in the Order.

The FAA has determined that this

proposed regulation only involves an

established body of technical

regulations for which frequent and

routine amendments are necessary to

keep them operationally current.

Therefore, this proposed regulation—(1)

is not a ‘‘significant regulatory action’’

under Executive Order 12866; (2) is not

a ‘‘significant rule’’ under DOT

Regulatory Policies and Procedures (44

FR 11034; February 26, 1979); and (3)

does not warrant preparation of a

regulatory evaluation as the anticipated

impact is so minimal. Since this is a

routine matter that would only affect air

traffic procedures and air navigation, it

is certified that this proposed rule

would not have significant economic

impact on a substantial number of small

entities under the criteria of the

Regulatory Flexibility Act.

List of Subjects in 14 CFR Part 71

Airspace, Incorporation by reference,

Navigation (air).

The Proposed Amendment

In consideration of the foregoing, the

Federal Aviation Administration

proposes to amend 14 CFR part 71 as

follows:

PART 71—[AMENDED]

1. The authority citation for 14 CFR

part 71 continues to read as follows:

Authority: 49 U.S.C. 106(g), 40103, 40113,

40120; E.O. 10854, 24 FR 9565, 3 CFR , 1959–

1963 Comp., p. 389.

§ 71.1 [Amended]

2. The incorporation by reference in

14 CFR 71.1 of Federal Aviation

Administration Order 7400.9H dated

September 1, 2000, and effective

September 16, 2000, is proposed to be

amended as follows:

Paragraph 6005 Class E airspace areas

extending upward from 700 feet or more

above the surface of the earth.

* * * * *

AEA PA E5 Couldersport, PA (New)

Charles Cole Memorial Hospital Heliport

Lat. 41°46′16.14′′ N/long. 77°58′28′′ W)

That airspace extending upward from 700

feet above the surface within a 6 mile radius

of the Charles Cole Memorial Hospital

Heliport.

* * * * *

Issued in Jamaica, New York, on May 15,

2001.

F.D. Hatfield,

Manager, Air Traffic Division, Eastern Region.

[FR Doc. 01–13311 Filed 5–25–01; 8:45 am]

BILLING CODE 4910–13–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 333

[Docket No. 96P–0460]

RIN 0910–AA01

Topical Antifungal Drug Products for

Over-the-Counter Human Use;

Proposed Amendment of Final

Monograph

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is issuing a

proposed rule that would amend the

final monograph for over-the-counter

(OTC) topical antifungal drug products

to add the ingredient clotrimazole as

generally recognized as safe and

effective for the treatment of athlete’s

foot, jock itch, and ringworm. This

proposal is part of FDA’s ongoing

review of OTC drug products.

DATES: Submit written comments by

August 27, 2001. Submit written

comments on the agency’s economic

impact determination by August 27,

2001. See section IX of this document

for the effective date of any final rule

that may publish based on this proposal.

ADDRESSES: Submit written comments

to the Docket Management Branch

(HFA–305), Food and Drug

Administration, 5630 Fishers Lane, rm.

1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Gerald M. Rachanow, Center for Drug

Evaluation and Research (HFD–560),

Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857,

301–827–2307.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of September

23, 1993 (58 FR 49890), FDA published

a final monograph for OTC topical

antifungal drug products in part 333 (21

CFR part 333), subpart C. That

monograph includes six antifungal

active ingredients used for the treatment

of athlete’s foot, jock itch, and ringworm

and one ingredient used for the

prevention of athlete’s foot. The

monograph provides that two

ingredients may contain professional

labeling (may be provided to health

professionals but not to the general

public) for the treatment of superficial

infections caused by yeast (Candida

albicans). A manufacturer submitted a

citizen petition (Refs. 1 through 4) to

include the antifungal ingredient

clotrimazole in the monograph for both

the OTC and professional labeling

treatment claims. Subsequently, the

manufacturer withdrew its request to

include clotrimazole in the monograph

for the professional labeling treatment

claim (Ref. 5).

II. The Agency’s Evaluation of the

Citizen Petition

A. General Background

Clotrimazole is a member of the

imidazole class of antifungal drugs and

is recognized in the U.S. Pharmacopeia

(Ref. 6). Clotrimazole has been marketed

as a topical antifungal at a 1-percent

concentration in the United States as a

prescription product since 1975 and as

an OTC product since 1989 under new

drug applications (NDAs) in cream,

lotion, and solution dosage forms. The

agency notes that clotrimazole has also

been marketed OTC in a number of

other countries, the first marketing

occurring in 1980. Distribution figures

(Ref. 1) indicate a significant amount of

the drug has been marketed OTC in the

United States and other countries since

1990. Miconazole nitrate, a related

member of the imidazole class of

antifungal drugs, is currently included

as an active ingredient in § 333.210(c) of

the final monograph for OTC topical

antifungal drug products.

B. Safety

The toxicity of clotrimazole has been

well-studied (Refs. 1 and 2). Acute

29060 Federal Register / Vol. 66, No. 103 / Tuesday, May 29, 2001 / Proposed Rules

toxicity has been studied in a variety of

animal species. When administered

intraperitoneally, the LD50 was

approximately 500 milligrams/kilogram

(mg/kg) for mice and 1,200 mg/kg for

rats. Subacute dermal toxicity studies in

rabbits (comparing clotrimazole cream

or solution to its vehicle) did not reveal

any significant dermal or systemic

changes. Other dermal tolerance studies

showed minimal irritation from

clotrimazole, and they showed that skin

reactions on rabbits were essentially the

same for the drug and the vehicle cream,

solution, or lotion. Ocular tolerance

studies in rabbits showed slight

conjunctival reddening and mild

irritation for both clotrimazole cream or

solution and its vehicle, which subsided

48 to 72 hours after instillation.

Studies have shown clotrimazole is

very poorly absorbed following dermal

application. Duhm et al. (Ref. 7)

reported that topical administration of

radiolabeled 1-percent clotrimazole

cream or solution to normal skin

resulted in less than 0.5 percent of the

activity excreted in the urine up to 5

days after application of the cream and

less than 0.05 percent up to 4 days after

application of the solution. When the

solution was applied to acutely

inflamed skin, 0.15 percent of the

activity was excreted in the urine. This

amount was slightly higher than after

applying the solution to normal skin. In

all subjects, urinary excretion was

largely completed 2 to 3 days after

application. No definitely measurable

amounts of radioactivity were found in

the serum of any of the subjects in

whom the radiolabeled clotrimazole

cream or solution was applied to intact

or inflamed skin until 48 hours after

application. The equivalent clotrimazole

concentrations were below the detection

limit of 0.001 microgram of clotrimazole

per milliliter (mL) of serum.

Reproduction studies in animals

showed, in general, that clotrimazole

was well tolerated and had no

teratogenic effect. All reproduction

studies (Ref. 1) were done with oral

dosing, 25 to 200 mg/kg in mice and rats

and 60 to 180 mg/kg in rabbits. The only

adverse effects noted were: (1) Lower

fetal weights and more resorptions in

rats given 100 mg/kg, and (2)

clotrimazole at 200 mg/kg was lethal to

pregnant rats. Mutagenic studies in

Chinese hamsters showed that

clotrimazole had no mutagenic effect.

An 18-month oral dosing study of

clotrimazole in rats did not show any

carcinogenic effect.

Clotrimazole has an excellent safety

record during its 24-year history of

marketing as a prescription and OTC

topical antifungal drug in the United

States. The manufacturer has reported

555 adverse drug events (ADEs) from

March 1975 through March 1996. Of

these, 240 (43 percent) are reports of

‘‘therapeutic response decrease’’ (lack of

effectiveness) with topical antifungal

treatment. The majority of the ADEs

were topical and nonserious in nature.

Pruritis (itching), rashes, erythema

(abnormal redness of the skin), and

paresthesia (abnormal sensation of the

skin, such as burning, stinging, or

tingling) were the most common events

reported and are common to all topical

antifungal drugs. Rarely, individuals

experienced a systemic allergic reaction.

The number and nature of reported

ADEs is similar before and after

clotrimazole OTC marketing in the

United States began in 1989.

The contact sensitization potential of

1-percent clotrimazole cream was

determined using the Maximization Test

(26 subjects) and the Draize Repeat

Insult Test (207 subjects) (Ref. 2). No

sensitization occurred in either test.

There are no known drug interactions,

abuse potential, or overdose potential

associated with clotrimazole when

applied topically to the skin for

antifungal use. There have been

infrequent reports of consumers

mistaking the solution (10 mL

container) product for eye drops and

instilling it in their eyes. All eye effects

reported have been minor and transient

and were completely relieved by

flushing the eye with water or the

passing of a short period of time.

Although these effects have been minor,

§ 333.250(c)(1)(iii) of the monograph for

OTC topical antifungal drug products

includes the warning: ‘‘Avoid contact

with the eyes.’’

C. Effectiveness

Clotrimazole has been shown in a

number of controlled studies to be an

effective OTC topical treatment for tinea

pedis (athlete’s foot), tinea cruris (jock

itch), and tinea corporis (ringworm).

The causative organisms in these

studies were primarily the same

organisms for which clotrimazole is

indicated: Trichophyton rubrum (T.

rubrum), Trichophyton mentagrophytes

(T. mentagrophytes), and

Epidermophyton floccosum (E.

floccosum).

Knox, Zaias, and Battistini (Refs. 2

and 3, Delbay 004) compared the

antifungal effectiveness of 1-percent

topical clotrimazole with its vehicle in

71 subjects (61 subsequently acceptable

for efficacy evaluation) who had

ringworm (16), jock itch (15), ringworm

and jock itch (7), and athlete’s foot (23).

The fungus infections were

mycologically confirmed by KOH

(potassium hydroxide) preparation and/

or culture. Subjects applied the assigned

products (double-blind, randomized,

parallel study) twice a day for 28 days

and were evaluated clinically weekly for

5 weeks, with samples taken each week

for KOH preparation and culture. Of the

61 cases (27 on active and 34 on

vehicle) evaluated, mycological

conversion rates (a change from positive

to negative of both KOH preparation and

culture) for tinea corporis/cruris were

76 percent (13/17) for active and 5

percent (1/21) for vehicle (P<0.001) and

for tinea pedis 60 percent (6/10) for

active and 0 (0/13) for vehicle (P=0.002).

The fungus most frequently detected

was T. rubrum. Eight of 12 subjects (67

percent) in the clotrimazole group who

had severe clinical signs and symptoms

were clinically cured compared to 0 of

14 in the vehicle group (P=0.0003).

Clayton and Connor (Refs. 2, 3, 4, and

8, Delbay 007) compared 1-percent

clotrimazole cream (50 subjects) to

Whitfield’s Ointment (3-percent

salicylic acid and 6-percent benzoic

acid) (52 subjects) and to nystatin

ointment (14 subjects) in treating several

fungal infections in a randomized,

double-blind trial based on the subject’s

condition. Subjects with mycologically

positive skin infection (by culture and/

or microscopy of skin scrapings) were

assigned to a test medication depending

on their diagnosis. The nystatin

ointment arm of the study did not

include any subjects with tinea

infections and, thus, is not discussed

further. Subjects with a fungal infection

applied clotrimazole cream or

Whitfield’s Ointment twice daily for 28

days. Followup examinations were

conducted at 2, 4, and 8 weeks for most

subjects. There were 100 evaluations of

subjects who had ringworm/jock itch

and athlete’s foot (some subjects had

both) and who applied clotrimazole or

Whitfield’s Ointment. Mycological

conversion rates for subjects with

ringworm/jock itch were 65 percent (13/

20) for clotrimazole and 63 percent (12/

19) for Whitfield’s Ointment (P=1.00),

and for subjects with athlete’s foot 63

percent (19/30) for clotrimazole and 58

percent (18/31) for Whitfield’s Ointment

(P=0.795). There were no statistically

significant differences between the

treatments, and the 1-percent

clotrimazole cream was considered as

effective as Whitfield’s Ointment, the

accepted treatment available at that

time, for treating tinea infections. The

investigators noted that there were a

greater number of side effects, usually

mild irritation or burning, with the

Whitfield’s Ointment (14 of 52 subjects)

than with the clotrimazole cream. Some

Federal Register / Vol. 66, No. 103 / Tuesday, May 29, 2001 / Proposed Rules 29061

subjects had no side effects, while

others had more than one. The total of

116 represents side effects recorded for

subjects at any visit.

Smith et al. (Refs. 2, 3, and 4, Delbay

003) compared the antifungal and

clinical effectiveness of 1-percent

clotrimazole topical solution against its

vehicle (polyethylene glycol 400) in a

randomized, double-blind study in 169

subjects, of which 131 were eventually

evaluated. Thirty eight subjects were

excluded from the study for various

reasons, with almost half of these lost to

followup. Fungal infections were

confirmed by KOH preparation and/or

culture; 120 subjects had fungal

infections (11 had candidiasis). Subjects

applied the test solutions twice daily for

28 days (65 used the active and 66 used

the vehicle). Effectiveness was

determined on the basis of mycological

findings, clinical findings (severity of

signs and symptoms), and overall

assessment of the treatment.

Mycological conversion rates for

subjects with tinea corporis/cruris were

96 percent (27/28) for the active and 34

percent (10/29) for the vehicle

(P<0.001). The conversion rates for

subjects with tinea pedis were 39

percent (12/31) for the active and 25

percent (8/32) for the vehicle. Weekly

sign and symptom severity was

evaluated on a scale of 1 (= none) to 4

(= severe). The weekly average for

clotrimazole subjects declined from 3.25

at week 0 to 1.82 at week 4, while

placebo declined from 3.14 to 2.52 for

the same times (P=0.009). The authors

stated that the treatment results clearly

demonstrated the mycological and

clinical effectiveness of the 1-percent

clotrimazole solution and that the

product was tolerated very well. The

agency has some concerns about the

usefulness of the clinical data as a scale

of weekly averages of signs and

symptoms. This information does not

enable a determination to be made

whether the subjects were actually

clinically cured or just clinically

improved. While the data lack sufficient

clinical meaning for the agency to

consider this a primary supportive

study, the agency considers this study

partially supportive of tinea corporis/

cruris claims, but not tinea pedis claims.

Tinea pedis claims are supported by

other studies discussed in this

document.

Smith and Knox (Refs. 2 and 3,

Delbay 005) used the clotrimazole

solution to continue to treat 22 subjects

from the previous study who failed to

respond mycologically to the vehicle

solution in an open, mycologically

controlled study with no control group.

The drug was applied twice a day for 2

to 6 weeks depending on the clinical

response. Eight subjects’ fungal

infections cleared completely both

mycologically and clinically; 4 became

negative mycologically and improved

clinically, but did not heal completely;

and 10 improved clinically but had

residual positive mycology. None of the

subjects reported any adverse events

due to the drug. The agency finds that

this study lacked sufficient details to be

useful to support effectiveness.

Eaglestein et al. (Refs. 2, 3, and 4,

Delbay 008) compared the antifungal

and clinical effectiveness of 1-percent

clotrimazole topical solution to its

vehicle in a study of 124 subjects with

tinea corporis/cruris using essentially

the same design as the Smith et al. study

(Delbay 003). Of these, 36 were not

included in the final evaluation (14

were lost to followup and 22 were

treated for a longer or shorter period

than the 4 weeks stipulated in the

protocol). Of the 88 subjects who met all

of the criteria for evaluation of

effectiveness, 29 had ringworm, 51 had

jock itch, and 8 had both conditions; 42

of these subjects used the active and 46

used the vehicle. After 28 days of

treatment, the mycological conversion

rates were 88 percent (37 of 42) for the

active and 28 percent (13 of 46) for the

vehicle (P<0.001). The primary fungus

detected was T. rubrum. The clinical

investigators evaluated overall severity

of clinical signs and symptoms (e.g.,

scaling, itching, inflammation) and

indicated that 40 of 41 clotrimazole

subjects improved clinically, compared

to 24 of 45 vehicle subjects (P<0.001).

One subject in each group could not be

evaluated in this regard because a

pretreatment severity was not specified.

The clinical investigators’ assessment of

the treatment was that 34 of 42

clotrimazole subjects were healed

clinically compared to 7 of 46 vehicle

subjects (P<0.001). The authors stated

that the results indicated that 1-percent

clotrimazole solution is very effective

for topical treatment of ringworm,

especially on smooth and bare skin. The

agency finds this study supportive of a

ringworm claim.

Eaglestein et al. (Refs. 2, 3, and 4,

Delbay 008) compared the anitfungal

and clinical effectiveness of 1-percent

clotrimazole topical solution to its

vehicle in a study of 124 subjects with

tinea corporis/crutis using essentially

the same design as the Smith et al. study

(Delbay 003). Eaglestein et al. (Ref. 2,

Delbay 011 and 012) compared the

antifungal and clinical effectiveness of

1-percent clotrimazole topical solution

to its vehicle in subjects with two

nonvesicular types of tinea pedis: (1)

Plantar hyperkeratosis (moccasin), and

(2) interdigital and/or instep, using the

same design as the Smith et al. study

(Delbay 003). The mycological

conversion rates for subjects with

plantar hyperkeratosis were 76 percent

(28 of 37) for the clotrimazole group and

39 percent (16 of 41) for the vehicle

group (P=0.001) and for subjects with

interdigital and/or instep were 66

percent (23 of 35) for the drug group and

39 percent (13 of 33) for the vehicle

group (P=0.026). Thirty of 37 (80

percent) drug treated subjects with

plantar hyperkeratosis improved

clinically compared to 24 of 41 (59

percent) vehicle subjects (P=0.027),

while 22 of 34 (65 percent) drug treated

subjects with interdigital and/or instep

improved clinically compared to 20 of

33 (61 percent) vehicle subjects (not

statistically significant). While the fungi

most frequently detected in the subjects

were T. rubrum and T. mentagrophytes,

organisms for which the drug is

indicated for OTC use, the OTC product

labeling does not include claims for

plantar hyperkeratosis or interdigital

and/or instep tinea pedis. Thus, these

studies provide support but do not

establish effectiveness for OTC use.

Fredriksson (Ref. 9) compared the

antifungal and clinical effectiveness of

1-percent clotrimazole topical solution

to its vehicle in a randomized, doubleblind, parallel study in 54 subjects. Half

of the subjects had tinea infections:

Tinea pedis (17), tinea cruris (8), tinea

corporis (1), and tinea capitis (1). T.

rubrum was the fungus most frequently

detected. The 27 subjects applied test

products (17 used clotrimazole and 10

used placebo) twice daily for 21 days, at

which time the study was decoded. The

10 vehicle-treated failures were then

crossed-over to an open study with

clotrimazole treatment for another 21

days. After 3 weeks of applying the 1-

percent clotrimazole solution, all 27

subjects (both the initial active group

and crossover vehicle failures) with

tinea infections were mycologically

cured, and 19 of the 27 subjects (70

percent) had no clinical evidence of

disease. The agency considers this study

supportive of effectiveness.

The Advisory Review Panel on OTC

Antimicrobial (II) Drug Products (the

Panel) discussed two studies involving

clotrimazole (Refs. 10 and 11) in its

evaluation of haloprogin (47 FR 12480

at 12493 and 12494, March 23, 1982).

One double-blind, clinical study (Ref.

10) compared the effectiveness of 1-

percent clotrimazole solution with 1-

percent haloprogin solution (the topical

antifungal drug product monograph

concentration in § 333.210(b)). Based on

the results of the study, the authors

concluded that clotrimazole was

29062 Federal Register / Vol. 66, No. 103 / Tuesday, May 29, 2001 / Proposed Rules

significantly more effective than

haloprogin for jock itch. The other

double-blind, randomized study (Ref.

11) compared 1-percent clotrimazole

cream and solution and 1-percent

haloprogin ointment and solution in the

treatment of subjects with athlete’s foot

and ringworm of the body. The author

concluded that there were no marked

differences in the antifungal

effectiveness of clotrimazole and

haloprogin.

D. Response to Comment

One comment (Ref. 12), submitted in

response to the citizen petition (Ref. 1),

opposed monograph status for

clotrimazole. The comment contended

that safety, effectiveness, and

therapeutic effect will not be assured

through the OTC drug monograph

process because neither bioequivalence

nor formulation changes will be

monitored by the agency. The comment

argued that topical antifungal drug

products present interesting formulation

and manufacturing issues and that the

agency could assure safety,

effectiveness, and interchangeability of

clotrimazole products only through its

application preapproval process. The

comment noted the Panel’s discussion

about vehicles for OTC topical

antifungal drug products (47 FR 12480

at 12489 and 12490). The Panel

discussed types and effects of different

vehicles, vehicle solubility and

viscosity, and the rate of diffusion of an

antifungal drug from a vehicle.

The agency disagrees with the

comment. The agency does not consider

the inclusion of clotrimazole in the

topical antifungal drug products

monograph at this time as any different

than the previous inclusion of the

former new drugs haloprogin and

miconazole nitrate in the monograph.

Bioequivalence testing is not required

for either of those drugs currently

marketed under the monograph. Based

on the previous monograph

determinations for haloprogin and

micinazole nitrate and the marketing of

clotrimazole OTC under NDA’s since

1989, the agency considers all three of

these ingredients to have an extensive

history of safe and effective OTC use.

While formulation and manufacturing

issues for topical products may prevent

FDA from allowing monograph status,

the agency has no evidence at this time

to indicate that formulation and

manufacturing issues have affected the

safety and effectiveness of clotrimazole.

The Panel’s discussion about vehicles

for these products was based on the

Panel’s general knowledge. Data on

specific vehicles were not submitted to

or reviewed by the Panel. No comments

were received on the Panel’s discussion

about vehicles for these products, and

this issue did not arise further in the

rulemaking in determining which

antifungal ingredients could be

included in the final monograph. The

agency monitors the quality of all

products marketed under OTC drug

monographs through its current good

manufacturing practice regulations in 21

CFR part 211 and its inspection

authority. If clotrimazole is marketed

under the final monograph, the agency

will monitor the quality of clotrimazole

products in the same manner as other

products currently marketed under the

monograph.

E. Labeling

Since 1989, antifungal drug products

containing clotrimazole 1 percent have

been marketed OTC in the United States

with indications for the treatment of

athlete’s foot (tinea pedis), jock itch

(tinea cruris), and ringworm (tinea

corporis). The warnings and directions

in the approved applications for these

products are very similar to those

contained in § 333.250(c) and (d) of the

final monograph for OTC antifungal

drug products. If a manufacturer

chooses to market its clotrimazole

product that is currently marketed OTC

under an approved application under

the monograph in the future, it will

have to modify the product’s labeling to

conform to the OTC drug monograph

labeling in § 333.250. In either case, the

manufacturer will need to follow the

new OTC drug content and format

labeling requirements in § 201.66 (21

CFR 201.66).

III. The Agency’s Tentative Conclusions

and Proposals

The agency has determined that

clotrimazole has been marketed to a

material extent and for a material time

as a topical antifungal drug and, based

on the available data, can be generally

recognized as safe and effective for this

use and included in the OTC drug

monograph for this class of products.

Therefore, the agency is proposing to

add clotrimazole 1 percent as new

paragraph (g) in § 333.210.

The agency is allowing interim

marketing of OTC topical antifungal

drug products containing 1-percent

clotrimazole with claims for the

treatment of athlete’s foot (tinea pedis),

jock itch (tinea cruris), and ringworm

(tinea corporis) to begin with the

publication of this proposal to amend

the monograph based on the OTC

marketing experience in the United

States since 1989 and because there are

no labeling issues to be addressed at this

time. Such interim marketing is subject

to the risk that the agency may adopt a

different position in the final rule that

could require relabeling, recall, or other

regulatory action. Any product

containing clotrimazole that is marketed

under the monograph before a final rule

is issued must use all of the labeling

that is required by the final monograph

(part 333, subpart C) and must follow

the content and format requirements in

§ 201.66.

This proposal does not apply to

clotrimazole marketed OTC as an

antifungal agent in intravaginal drug

products labeled for the treatment of

vaginal yeast infections. The existing

monograph for topical antifungal drug

products does not contain any claims

for intravaginal use.

IV. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Comment No. CP1, Docket No. 96P–

0460, Dockets Management Branch.

2. Comment No. SUP1, Docket No. 96P–

0460, Dockets Management Branch.

3. Comment No. LET3, Docket No. 96P–

0460, Dockets Management Branch.

4. Comment No. LET4, Docket No. 96P–

0460, Dockets Management Branch.

5. Comment No. LET5, Docket No. 96P–

0460, Dockets Management Branch.

6. The United States Pharmacopeia 24–The

National Formulary 19, The United States

Pharmacopeial Convention, Inc., Rockville,

MD, p. 451, 1999.

7. Duhm, B. et al., ‘‘Pharmacokinetics of

Topically Applied Bisphenyl-(2-

chlorophenyl) -1-imidazolyl-methane-[14C],’’

Arzneittelforschung, 22:1289–191, 1972,

English version, Drugs Made in Germany,

15:126–132, 1972.

8. Clayton, Y. M. and B. L. Connor,

‘‘Comparison of Clotrimazole Cream,

Whitfield’s Ointment and Nystatin Ointment

for the Topical Treatment of Ringworm

Infections, Pityriasis Versicolor, Erythrasma,

and Candidiasis,’’ British Journal of

Dermatology, 89:297–303, 1973.

9. Fredriksson, T., ‘‘Topical Treatment

with Bay b 5097, A New Broad Spectrum

Antimycotic Agent,’’ British Journal of

Dermatology, 86:628–630, 1972.

10. Van Dersarl, J. V. and R. H. Sheppard,

‘‘Clotrimazole vs. Haloprogin Treatment of

Tinea Cruris,’’ Archives of Dermatology,

113:1233–1235, 1977.

11. Weitgasser, H., ‘‘Clinical and Mycologic

Trials with the Antifungal Medication

Haloprogin,’’ Mykosen, 20:15–24, 1977.

12. Comment No. C1, Docket No. 96P–

0460, Dockets Management Branch.

V. Analysis of Impacts

FDA has examined the impacts of this

proposed rule under Executive Order

12866, the Regulatory Flexibility Act (5

Federal Register / Vol. 66, No. 103 / Tuesday, May 29, 2001 / Proposed Rules 29063

U.S.C. 601–612) (as amended by subtitle

D of the Small Business and Regulatory

Fairness Act of 1996 (Public Law 104–

121)), and the Unfunded Mandates

Reform Act of 1995 (Public Law 104–4)

(2 U.S.C. 1501 et seq.). 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.

Section 202(a) of the Unfunded

Mandates Reform Act requires that

agencies prepare a written statement

and economic analysis before proposing

any rule that may result in an

expenditure in any one year by State,

local, and tribal governments, in the

aggregate, or by the private sector, of

$100 million (adjusted annually for

inflation).

The agency believes that this

proposed rule is consistent with the

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, as explained

below, and so is not subject to review

under the Executive Order.

The purpose of this proposed rule is

to include clotrimazole 1 percent in the

monograph for OTC topical antifungal

drug products. This proposal allows

current manufacturers of these products

to market their products under the OTC

drug monograph instead of an NDA and

enables other manufacturers who wish

to market clotrimazole products OTC to

enter the marketplace without having to

obtain an NDA. In both cases, there will

be cost savings from marketing without

an NDA.

If current manufacturers of these

products choose to market them under

the OTC drug monograph, they should

incur only minor costs to relabel their

products to meet the monograph. Some

manufacturers may have to add a

warning that was included in the final

monograph, but not required when

some products containing clotrimazole

were approved for OTC marketing under

an NDA. These manufacturers can make

this change whenever they are ready to

order new product labeling.

Manufacturers have informed the

agency that this type of relabeling cost

generally averages about $2,000 to

$3,000 per stock keeping unit (SKU)

(individual products, packages, and

sizes). Based on information in the

agency’s Drug Listing System, there are

less than 10 manufacturers and

distributors that together produce about

25 SKU’s of OTC topical antifungal drug

products that contain clotrimazole.

Assuming that there are about 25

affected OTC SKU’s in the marketplace,

total one-time costs of relabeling would

be $50,000 to $75,000 if the

manufacturers of these products

changed their marketing from under an

approved application to under the OTC

drug monograph. In making this change,

these manufacturers would save money

by eliminating all costs associated with

maintaining an application. Likewise,

other manufacturers who now wish to

market topical clotrimazole drug

products will be able to enter the

marketplace without the costs

associated with an application. Their

costs would involve the standard startup costs of any OTC drug marketed

under the monograph.

The agency considered but rejected

several alternatives: (1) Not including

clotrimazole in the monograph, (2) a

longer implementation period, and (3)

no interim marketing. The agency

rejected the first alternative because it

considers the data presented supportive

of monograph status. The agency does

not see a need for the second or third

alternatives because these clotrimazole

drug products are already marketed

OTC under approved applications and

compendial standards currently exist for

clotrimazole. The agency does not

consider an exemption for small entities

necessary because those manufacturers

can enter the marketplace under the

monograph at any time.

Under the Unfunded Mandates

Reform Act, FDA is not required to

prepare a statement of costs and benefits

for this proposed rule because this

proposed rule is not expected to result

in any one-year expenditure that would

exceed $100 million adjusted for

inflation.

This analysis shows that the agency

has considered the burden to small

entities. Thus, this economic analysis,

together with other relevant sections of

this document, serves as the agency’s

initial regulatory flexibility analysis, as

required under the Regulatory

Flexibility Act.

VI. Paperwork Reduction Act of 1995

FDA tentatively concludes that the

labeling requirements for clotrimazole

are not subject to review by the Office

of Management and Budget because

they do not constitute a ‘‘collection of

information’’ under the Paperwork

Reduction Act of 1995 (44 U.S.C. 3501

et seq.). Rather, the existing monograph

labeling is a ‘‘public disclosure of

information originally supplied by the

Federal Government to the recipient for

the purpose of disclosure to the public’’

(5 CFR 1320.3(c)(2)).

VII. Environmental Impact

The agency has determined under 21

CFR 25.31(a) 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.

VIII. Request for Comments

Interested persons may submit to the

Dockets Management Branch (address

above) written comments regarding the

proposal by August 27, 2001. Written

comments on the agency’s economic

impact determination may be submitted

on or before August 27, 2001. Three

copies of all comments are to be

submitted, except that individuals may

submit one copy. Comments are to be

identified with the docket number

found in brackets in the heading of this

document and may be accompanied by

a supporting memorandum or brief.

Received comments may be seen in the

office above between 9 a.m. and 4 p.m.,

Monday through Friday.

IX. Proposed Effective Date

The agency is proposing that any final

rule that may issue based on this

proposal become effective 30 days after

its date of publication in the Federal

Register.

List of Subjects in 21 CFR Part 333

Labeling, Over-the-counter drugs.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR part 333 be amended as follows:

PART 333—TOPICAL ANTIMICROBIAL

DRUG PRODUCTS FOR OVER-THECOUNTER HUMAN USE

1. The authority citation for 21 CFR

part 333 continues to read as follows:

Authority: 21 U.S.C. 321, 351, 352, 353,

355, 360, 371.

2. Section 333.210 is amended by

adding paragraph (g) to read as follows:

§ 333.210 Antifungal active ingredients.

* * * * *

(g) Clotrimazole 1 percent.

29064 Federal Register / Vol. 66, No. 103 / Tuesday, May 29, 2001 / Proposed Rules

Dated: May 17, 2001.

Margaret M. Dotzel,

Associate Commissioner for Policy.

[FR Doc. 01–13299 Filed 5–25–01; 8:45 am]

BILLING CODE 4160–01–S

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 52

[PA 169—4116; FRL–6986–8]

Approval and Promulgation of Air

Quality Implementation Plans;

Pennsylvania; Nitrogen Oxides Budget

Trading Program

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: EPA is proposing to approve

a State Implementation Plan (SIP)

revision submitted by the

Commonwealth of Pennsylvania on

October 30, 2000 and April 4, 2001.

This revision responds to the EPA’s

regulation entitled, ‘‘Finding of

Significant Contribution and

Rulemaking for Certain States in the

Ozone Transport Assessment Group

Region for Purposes of Reducing

Regional Transport of Ozone,’’

otherwise known as the ‘‘NOX SIP Call.’’

This revision establishes and requires a

nitrogen oxides (NOX) allowance trading

program for large electric generating and

industrial units, beginning in 2003. The

intended effect of this action is to

propose approval the Pennsylvania NOX

Budget Trading Program because it

addresses the requirements of the NOX

SIP Call Phase I that will significantly

reduce ozone transport in the eastern

United States. EPA is proposing to

approve this revision in accordance

with the requirements of the Clean Air

Act.

DATES: Written comments must be

received on or before June 28, 2001.

ADDRESSES: Written comments should

be mailed to David L. Arnold, Chief, Air

Quality Planning and Information

Services Branch, Mailcode 3AP21, U.S.

Environmental Protection Agency,

Region III, 1650 Arch Street,

Philadelphia, Pennsylvania 19103.

Copies of the documents relevant to this

action are available for public

inspection during normal business

hours at the Air Protection Division,

U.S. Environmental Protection Agency,

Region III, 1650 Arch Street,

Philadelphia, Pennsylvania 19103; and

Pennsylvania Department of

Environmental Protection, Bureau of Air

Quality, P.O. Box 8468, 400 Market

Street, Harrisburg, Pennsylvania 17105.

FOR FURTHER INFORMATION CONTACT:

Cristina Fernandez, (215) 814–2178, or

by e-mail at fernandez.cristina@epa.gov.

SUPPLEMENTARY INFORMATION: On

October 30, 2000 and April 4, 2001, the

Pennsylvania Department of

Environmental Protection (PADEP)

submitted a revision to the

Pennsylvania SIP to address the

requirements of the NOX SIP Call Phase

I. The information in this section is

organized as follows:

I. EPA’s Action

A. What action is EPA proposing today?

B. Why is EPA proposing this action?

C. What are the general NOX SIP Call

requirements?

D. What is EPA’s NOX budget trading

program?

E. What guidance did EPA use to evaluate

Pennsylvania’s submittal?

II. Pennsylvania’s NOX Budget Trading

Program

A. When did Pennsylvania submit the SIP

revision to EPA in response to the NOX

SIP Call?

B. What is the Pennsylvania NOX Budget

Trading Program?

C. What is the result of EPA’s evaluation of

Pennsylvania’s program?

III. Proposed Action

A. NOX SIP Call Requirements

B. One-Hour Attainment Demonstration

Plans

IV. Administrative Requirements

I. EPA’s Action

A. What Action Is EPA Proposing

Today?

EPA is proposing to approve the

Pennsylvania SIP revision concerning

the adoption of its NOX Budget Trading

Program, submitted on October 30, 2000

and April 4, 2001.

B. Why Is EPA Proposing This Action?

EPA is proposing this action for two

purposes. Pennsylvania’s NOX Budget

Trading Program regulations address the

requirements of the NOX SIP Call Phase

I. In addition, Pennsylvania’s NOX

Budget Trading Program regulations are

part of the Pennsylvania one-hour ozone

attainment demonstration plan for the

Philadelphia-Wilmington-Trenton

severe ozone nonattainment area. The

Pennsylvania one-hour attainment

demonstration plan for the

Philadelphia-Wilmington-Trenton

ozone nonattainment area relies on the

NOX reductions associated with the

NOX Budget Trading Program in 2003

and beyond. Therefore, EPA is

proposing to approve Pennsylvania’s

NOX Budget Trading Program for two

reasons. First, because it addresses the

requirements of the NOX SIP Call Phase

I, and secondly as a strengthening

measure for the one-hour ozone

standard attainment for PhiladelphiaWilmington-Trenton ozone

nonattainment area.

C. What Are the General NOX SIP Call

Requirements?

On October 27, 1998, EPA published

a final rule entitled, ‘‘Finding of

Significant Contribution and

Rulemaking for Certain States in the

Ozone Transport Assessment Group

Region for Purposes of Reducing

Regional Transport of Ozone,’’

otherwise known as the ‘‘NOX SIP Call.’’

See 63 FR 57356. The NOX SIP Call

requires 22 States and the District of

Columbia to meet statewide NOX

emission budgets during the five month

period between May 1 and October 1 in

order to reduce the amount of ground

level ozone that is transported across

the eastern United States.

EPA determined state-wide NOX

emission budgets for each affected

jurisdiction to be met by the year 2007.

EPA identified NOX emission

reductions by source category that could

be achieved by using cost-effective

measures. The source categories

included were electric generating units

(EGUs), non-electric generating units

(non-EGUs), area sources, nonroad

mobile sources and highway sources.

However, the NOX SIP Call allowed

states the flexibility to decide which

source categories to regulate in order to

meet the statewide budgets. In the NOX

SIP Call notice, EPA suggested that

imposing statewide NOX emissions caps

on large fossil-fuel fired industrial

boilers and electricity generating units

would provide a highly cost effective

means for States to meet their NOX

budgets. In fact, the state-specific

budgets were set assuming an emission

rate of 0.15 pounds NOX per million

British thermal units (lb. NOX/mmBtu)

at EGUs, multiplied by the projected

heat input (mmBtu) from burning the

quantity of fuel needed to meet the 2007

forecast for electricity demand. See 63

FR 57407. The calculation of the 2007

EGU emissions assumed that an

emissions trading program would be

part of an EGU control program. The

NOX SIP Call state budgets also assumed

on average a 30% NOX reduction from

cement kilns, a 60% reduction from

industrial boilers and combustion

turbines, and a 90% reduction from

internal combustion engines. The nonEGU control assumptions were applied

at units where the heat input capacities

were greater than 250 mmBtu per hour,

or in cases where heat input data were