Federal Register / Vol. 66, No. 103 / Tuesday, May 29, 2001 / Proposed Rules 29059
notice number of this NPRM. Persons § 71.1 [Amended] Administration, 5630 Fishers Lane, rm. interested in being placed on a mailing 2. The incorporation by reference in 1061, Rockville, MD 20852. list for future NPRMs should also 14 CFR 71.1 of Federal Aviation FOR FURTHER INFORMATION CONTACT: request a copy of Advisory Circular No. Administration Order 7400.9H dated Gerald M. Rachanow, Center for Drug 11–2A, which describes the application September 1, 2000, and effective Evaluation and Research (HFD–560), procedure. September 16, 2000, is proposed to be Food and Drug Administration, 5600 The Proposal amended as follows: Fishers Lane, Rockville, MD 20857, 301–827–2307. The FAA is considering an Paragraph 6005 Class E airspace areas extending upward from 700 feet or more SUPPLEMENTARY INFORMATION: amendment to Part 71 of the Federal above the surface of the earth. Aviaiton Regulations (14 CFR part 71) to I. Background * * * * * establish Class E airspace area at In the Federal Register of September Couldersport, PA. An RNAV Approach, AEA PA E5 Couldersport, PA (New) 23, 1993 (58 FR 49890), FDA published Helicopter RNAV 343, has been Charles Cole Memorial Hospital Heliport a final monograph for OTC topical developed for Charles Cole Memorial Lat. 41°46′16.14″ N/long. 77°58′28″ W) antifungal drug products in part 333 (21 Hospital Heliport, Couldersport, PA. That airspace extending upward from 700 CFR part 333), subpart C. That Controlled airspace extending upward feet above the surface within a 6 mile radius monograph includes six antifungal from 700 feet AGL is needed to of the Charles Cole Memorial Hospital active ingredients used for the treatment accommodate the SIAP. Class E airspace Heliport. of athlete’s foot, jock itch, and ringworm designations for airspace areas * * * * * and one ingredient used for the extending upward from 700 feet from or Issued in Jamaica, New York, on May 15, prevention of athlete’s foot. The above the surface are published in 2001. monograph provides that two Paragraph 6005 of FAA Order 7400.9H, F.D. Hatfield, ingredients may contain professional dated September 1, 2000, and effective Manager, Air Traffic Division, Eastern Region. labeling (may be provided to health September 16, 2000, which is professionals but not to the general [FR Doc. 01–13311 Filed 5–25–01; 8:45 am] incorporated by reference in 14 CFR public) for the treatment of superficial 71.1. The Class E airspace designation BILLING CODE 4910–13–M infections caused by yeast (Candida listed in this document would be albicans). A manufacturer submitted a published subsequently in the Order. citizen petition (Refs. 1 through 4) to The FAA has determined that this DEPARTMENT OF HEALTH AND include the antifungal ingredient proposed regulation only involves an HUMAN SERVICES clotrimazole in the monograph for both established body of technical Food and Drug Administration the OTC and professional labeling regulations for which frequent and treatment claims. Subsequently, the routine amendments are necessary to 21 CFR Part 333 manufacturer withdrew its request to keep them operationally current. include clotrimazole in the monograph Therefore, this proposed regulation—(1) [Docket No. 96P–0460] for the professional labeling treatment is not a ‘‘significant regulatory action’’ claim (Ref. 5). under Executive Order 12866; (2) is not RIN 0910–AA01 a ‘‘significant rule’’ under DOT II. The Agency’s Evaluation of the Topical Antifungal Drug Products for Citizen Petition Regulatory Policies and Procedures (44 Over-the-Counter Human Use; FR 11034; February 26, 1979); and (3) Proposed Amendment of Final A. General Background does not warrant preparation of a Monograph Clotrimazole is a member of the regulatory evaluation as the anticipated imidazole class of antifungal drugs and impact is so minimal. Since this is a AGENCY: Food and Drug Administration, is recognized in the U.S. Pharmacopeia routine matter that would only affect air HHS. (Ref. 6). Clotrimazole has been marketed traffic procedures and air navigation, it ACTION: Proposed rule. as a topical antifungal at a 1-percent is certified that this proposed rule concentration in the United States as a would not have significant economic SUMMARY: The Food and Drug prescription product since 1975 and as impact on a substantial number of small Administration (FDA) is issuing a an OTC product since 1989 under new entities under the criteria of the proposed rule that would amend the drug applications (NDAs) in cream, Regulatory Flexibility Act. final monograph for over-the-counter (OTC) topical antifungal drug products lotion, and solution dosage forms. The List of Subjects in 14 CFR Part 71 to add the ingredient clotrimazole as agency notes that clotrimazole has also Airspace, Incorporation by reference, generally recognized as safe and been marketed OTC in a number of Navigation (air). effective for the treatment of athlete’s other countries, the first marketing foot, jock itch, and ringworm. This occurring in 1980. Distribution figures The Proposed Amendment proposal is part of FDA’s ongoing (Ref. 1) indicate a significant amount of In consideration of the foregoing, the review of OTC drug products. the drug has been marketed OTC in the Federal Aviation Administration United States and other countries since DATES: Submit written comments by 1990. Miconazole nitrate, a related proposes to amend 14 CFR part 71 as August 27, 2001. Submit written follows: member of the imidazole class of comments on the agency’s economic antifungal drugs, is currently included impact determination by August 27, PART 71—[AMENDED] as an active ingredient in § 333.210(c) of 2001. See section IX of this document the final monograph for OTC topical 1. The authority citation for 14 CFR for the effective date of any final rule antifungal drug products. part 71 continues to read as follows: that may publish based on this proposal. B. Safety Authority: 49 U.S.C. 106(g), 40103, 40113, ADDRESSES: Submit written comments 40120; E.O. 10854, 24 FR 9565, 3 CFR , 1959– to the Docket Management Branch The toxicity of clotrimazole has been 1963 Comp., p. 389. (HFA–305), Food and Drug well-studied (Refs. 1 and 2). Acute
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toxicity has been studied in a variety of States. The manufacturer has reported (potassium hydroxide) preparation and/ animal species. When administered 555 adverse drug events (ADEs) from or culture. Subjects applied the assigned intraperitoneally, the LD50 was March 1975 through March 1996. Of products (double-blind, randomized, approximately 500 milligrams/kilogram these, 240 (43 percent) are reports of parallel study) twice a day for 28 days (mg/kg) for mice and 1,200 mg/kg for ‘‘therapeutic response decrease’’ (lack of and were evaluated clinically weekly for rats. Subacute dermal toxicity studies in effectiveness) with topical antifungal 5 weeks, with samples taken each week rabbits (comparing clotrimazole cream treatment. The majority of the ADEs for KOH preparation and culture. Of the or solution to its vehicle) did not reveal were topical and nonserious in nature. 61 cases (27 on active and 34 on any significant dermal or systemic Pruritis (itching), rashes, erythema vehicle) evaluated, mycological changes. Other dermal tolerance studies (abnormal redness of the skin), and conversion rates (a change from positive showed minimal irritation from paresthesia (abnormal sensation of the to negative of both KOH preparation and clotrimazole, and they showed that skin skin, such as burning, stinging, or culture) for tinea corporis/cruris were reactions on rabbits were essentially the tingling) were the most common events 76 percent (13/17) for active and 5 same for the drug and the vehicle cream, reported and are common to all topical percent (1/21) for vehicle (P<0.001) and solution, or lotion. Ocular tolerance antifungal drugs. Rarely, individuals for tinea pedis 60 percent (6/10) for studies in rabbits showed slight experienced a systemic allergic reaction. active and 0 (0/13) for vehicle (P=0.002). conjunctival reddening and mild The number and nature of reported The fungus most frequently detected irritation for both clotrimazole cream or ADEs is similar before and after was T. rubrum. Eight of 12 subjects (67 solution and its vehicle, which subsided clotrimazole OTC marketing in the percent) in the clotrimazole group who 48 to 72 hours after instillation. United States began in 1989. had severe clinical signs and symptoms Studies have shown clotrimazole is The contact sensitization potential of were clinically cured compared to 0 of very poorly absorbed following dermal 1-percent clotrimazole cream was 14 in the vehicle group (P=0.0003). application. Duhm et al. (Ref. 7) determined using the Maximization Test Clayton and Connor (Refs. 2, 3, 4, and reported that topical administration of (26 subjects) and the Draize Repeat 8, Delbay 007) compared 1-percent radiolabeled 1-percent clotrimazole Insult Test (207 subjects) (Ref. 2). No clotrimazole cream (50 subjects) to cream or solution to normal skin sensitization occurred in either test. Whitfield’s Ointment (3-percent resulted in less than 0.5 percent of the There are no known drug interactions, salicylic acid and 6-percent benzoic activity excreted in the urine up to 5 abuse potential, or overdose potential acid) (52 subjects) and to nystatin days after application of the cream and associated with clotrimazole when less than 0.05 percent up to 4 days after applied topically to the skin for ointment (14 subjects) in treating several application of the solution. When the antifungal use. There have been fungal infections in a randomized, solution was applied to acutely infrequent reports of consumers double-blind trial based on the subject’s inflamed skin, 0.15 percent of the mistaking the solution (10 mL condition. Subjects with mycologically activity was excreted in the urine. This container) product for eye drops and positive skin infection (by culture and/ amount was slightly higher than after instilling it in their eyes. All eye effects or microscopy of skin scrapings) were applying the solution to normal skin. In reported have been minor and transient assigned to a test medication depending all subjects, urinary excretion was and were completely relieved by on their diagnosis. The nystatin largely completed 2 to 3 days after flushing the eye with water or the ointment arm of the study did not application. No definitely measurable passing of a short period of time. include any subjects with tinea amounts of radioactivity were found in Although these effects have been minor, infections and, thus, is not discussed the serum of any of the subjects in § 333.250(c)(1)(iii) of the monograph for further. Subjects with a fungal infection whom the radiolabeled clotrimazole OTC topical antifungal drug products applied clotrimazole cream or cream or solution was applied to intact includes the warning: ‘‘Avoid contact Whitfield’s Ointment twice daily for 28 or inflamed skin until 48 hours after with the eyes.’’ days. Followup examinations were application. The equivalent clotrimazole conducted at 2, 4, and 8 weeks for most C. Effectiveness concentrations were below the detection subjects. There were 100 evaluations of limit of 0.001 microgram of clotrimazole Clotrimazole has been shown in a subjects who had ringworm/jock itch per milliliter (mL) of serum. number of controlled studies to be an and athlete’s foot (some subjects had Reproduction studies in animals effective OTC topical treatment for tinea both) and who applied clotrimazole or showed, in general, that clotrimazole pedis (athlete’s foot), tinea cruris (jock Whitfield’s Ointment. Mycological was well tolerated and had no itch), and tinea corporis (ringworm). conversion rates for subjects with teratogenic effect. All reproduction The causative organisms in these ringworm/jock itch were 65 percent (13/ studies (Ref. 1) were done with oral studies were primarily the same 20) for clotrimazole and 63 percent (12/ dosing, 25 to 200 mg/kg in mice and rats organisms for which clotrimazole is 19) for Whitfield’s Ointment (P=1.00), and 60 to 180 mg/kg in rabbits. The only indicated: Trichophyton rubrum (T. and for subjects with athlete’s foot 63 adverse effects noted were: (1) Lower rubrum), Trichophyton mentagrophytes percent (19/30) for clotrimazole and 58 fetal weights and more resorptions in (T. mentagrophytes), and percent (18/31) for Whitfield’s Ointment rats given 100 mg/kg, and (2) Epidermophyton floccosum (E. (P=0.795). There were no statistically clotrimazole at 200 mg/kg was lethal to floccosum). significant differences between the pregnant rats. Mutagenic studies in Knox, Zaias, and Battistini (Refs. 2 treatments, and the 1-percent Chinese hamsters showed that and 3, Delbay 004) compared the clotrimazole cream was considered as clotrimazole had no mutagenic effect. antifungal effectiveness of 1-percent effective as Whitfield’s Ointment, the An 18-month oral dosing study of topical clotrimazole with its vehicle in accepted treatment available at that clotrimazole in rats did not show any 71 subjects (61 subsequently acceptable time, for treating tinea infections. The carcinogenic effect. for efficacy evaluation) who had investigators noted that there were a Clotrimazole has an excellent safety ringworm (16), jock itch (15), ringworm greater number of side effects, usually record during its 24-year history of and jock itch (7), and athlete’s foot (23). mild irritation or burning, with the marketing as a prescription and OTC The fungus infections were Whitfield’s Ointment (14 of 52 subjects) topical antifungal drug in the United mycologically confirmed by KOH than with the clotrimazole cream. Some
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subjects had no side effects, while to 6 weeks depending on the clinical (2) interdigital and/or instep, using the others had more than one. The total of response. Eight subjects’ fungal same design as the Smith et al. study 116 represents side effects recorded for infections cleared completely both (Delbay 003). The mycological subjects at any visit. mycologically and clinically; 4 became conversion rates for subjects with Smith et al. (Refs. 2, 3, and 4, Delbay negative mycologically and improved plantar hyperkeratosis were 76 percent 003) compared the antifungal and clinically, but did not heal completely; (28 of 37) for the clotrimazole group and clinical effectiveness of 1-percent and 10 improved clinically but had 39 percent (16 of 41) for the vehicle clotrimazole topical solution against its residual positive mycology. None of the group (P=0.001) and for subjects with vehicle (polyethylene glycol 400) in a subjects reported any adverse events interdigital and/or instep were 66 randomized, double-blind study in 169 due to the drug. The agency finds that percent (23 of 35) for the drug group and subjects, of which 131 were eventually this study lacked sufficient details to be 39 percent (13 of 33) for the vehicle evaluated. Thirty eight subjects were useful to support effectiveness. group (P=0.026). Thirty of 37 (80 excluded from the study for various Eaglestein et al. (Refs. 2, 3, and 4, percent) drug treated subjects with reasons, with almost half of these lost to Delbay 008) compared the antifungal plantar hyperkeratosis improved followup. Fungal infections were and clinical effectiveness of 1-percent clinically compared to 24 of 41 (59 confirmed by KOH preparation and/or clotrimazole topical solution to its percent) vehicle subjects (P=0.027), culture; 120 subjects had fungal vehicle in a study of 124 subjects with while 22 of 34 (65 percent) drug treated infections (11 had candidiasis). Subjects tinea corporis/cruris using essentially subjects with interdigital and/or instep applied the test solutions twice daily for the same design as the Smith et al. study improved clinically compared to 20 of 28 days (65 used the active and 66 used (Delbay 003). Of these, 36 were not 33 (61 percent) vehicle subjects (not the vehicle). Effectiveness was included in the final evaluation (14 statistically significant). While the fungi determined on the basis of mycological were lost to followup and 22 were most frequently detected in the subjects findings, clinical findings (severity of treated for a longer or shorter period were T. rubrum and T. mentagrophytes, signs and symptoms), and overall than the 4 weeks stipulated in the organisms for which the drug is assessment of the treatment. protocol). Of the 88 subjects who met all indicated for OTC use, the OTC product Mycological conversion rates for of the criteria for evaluation of labeling does not include claims for subjects with tinea corporis/cruris were effectiveness, 29 had ringworm, 51 had plantar hyperkeratosis or interdigital 96 percent (27/28) for the active and 34 jock itch, and 8 had both conditions; 42 and/or instep tinea pedis. Thus, these percent (10/29) for the vehicle of these subjects used the active and 46 studies provide support but do not (P<0.001). The conversion rates for used the vehicle. After 28 days of establish effectiveness for OTC use. subjects with tinea pedis were 39 treatment, the mycological conversion Fredriksson (Ref. 9) compared the percent (12/31) for the active and 25 rates were 88 percent (37 of 42) for the antifungal and clinical effectiveness of percent (8/32) for the vehicle. Weekly active and 28 percent (13 of 46) for the 1-percent clotrimazole topical solution sign and symptom severity was vehicle (P<0.001). The primary fungus to its vehicle in a randomized, double- evaluated on a scale of 1 (= none) to 4 detected was T. rubrum. The clinical blind, parallel study in 54 subjects. Half (= severe). The weekly average for investigators evaluated overall severity of the subjects had tinea infections: clotrimazole subjects declined from 3.25 of clinical signs and symptoms (e.g., Tinea pedis (17), tinea cruris (8), tinea at week 0 to 1.82 at week 4, while scaling, itching, inflammation) and corporis (1), and tinea capitis (1). T. placebo declined from 3.14 to 2.52 for indicated that 40 of 41 clotrimazole rubrum was the fungus most frequently the same times (P=0.009). The authors subjects improved clinically, compared detected. The 27 subjects applied test stated that the treatment results clearly to 24 of 45 vehicle subjects (P<0.001). products (17 used clotrimazole and 10 demonstrated the mycological and One subject in each group could not be used placebo) twice daily for 21 days, at clinical effectiveness of the 1-percent evaluated in this regard because a which time the study was decoded. The clotrimazole solution and that the pretreatment severity was not specified. 10 vehicle-treated failures were then product was tolerated very well. The The clinical investigators’ assessment of crossed-over to an open study with agency has some concerns about the the treatment was that 34 of 42 clotrimazole treatment for another 21 usefulness of the clinical data as a scale clotrimazole subjects were healed days. After 3 weeks of applying the 1- of weekly averages of signs and clinically compared to 7 of 46 vehicle percent clotrimazole solution, all 27 symptoms. This information does not subjects (P<0.001). The authors stated subjects (both the initial active group enable a determination to be made that the results indicated that 1-percent and crossover vehicle failures) with whether the subjects were actually clotrimazole solution is very effective tinea infections were mycologically clinically cured or just clinically for topical treatment of ringworm, cured, and 19 of the 27 subjects (70 improved. While the data lack sufficient especially on smooth and bare skin. The percent) had no clinical evidence of clinical meaning for the agency to agency finds this study supportive of a disease. The agency considers this study consider this a primary supportive ringworm claim. supportive of effectiveness. study, the agency considers this study Eaglestein et al. (Refs. 2, 3, and 4, The Advisory Review Panel on OTC partially supportive of tinea corporis/ Delbay 008) compared the anitfungal Antimicrobial (II) Drug Products (the cruris claims, but not tinea pedis claims. and clinical effectiveness of 1-percent Panel) discussed two studies involving Tinea pedis claims are supported by clotrimazole topical solution to its clotrimazole (Refs. 10 and 11) in its other studies discussed in this vehicle in a study of 124 subjects with evaluation of haloprogin (47 FR 12480 document. tinea corporis/crutis using essentially at 12493 and 12494, March 23, 1982). Smith and Knox (Refs. 2 and 3, the same design as the Smith et al. study One double-blind, clinical study (Ref. Delbay 005) used the clotrimazole (Delbay 003). Eaglestein et al. (Ref. 2, 10) compared the effectiveness of 1- solution to continue to treat 22 subjects Delbay 011 and 012) compared the percent clotrimazole solution with 1- from the previous study who failed to antifungal and clinical effectiveness of percent haloprogin solution (the topical respond mycologically to the vehicle 1-percent clotrimazole topical solution antifungal drug product monograph solution in an open, mycologically to its vehicle in subjects with two concentration in § 333.210(b)). Based on controlled study with no control group. nonvesicular types of tinea pedis: (1) the results of the study, the authors The drug was applied twice a day for 2 Plantar hyperkeratosis (moccasin), and concluded that clotrimazole was
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significantly more effective than were received on the Panel’s discussion to the risk that the agency may adopt a haloprogin for jock itch. The other about vehicles for these products, and different position in the final rule that double-blind, randomized study (Ref. this issue did not arise further in the could require relabeling, recall, or other 11) compared 1-percent clotrimazole rulemaking in determining which regulatory action. Any product cream and solution and 1-percent antifungal ingredients could be containing clotrimazole that is marketed haloprogin ointment and solution in the included in the final monograph. The under the monograph before a final rule treatment of subjects with athlete’s foot agency monitors the quality of all is issued must use all of the labeling and ringworm of the body. The author products marketed under OTC drug that is required by the final monograph concluded that there were no marked monographs through its current good (part 333, subpart C) and must follow differences in the antifungal manufacturing practice regulations in 21 the content and format requirements in effectiveness of clotrimazole and CFR part 211 and its inspection § 201.66. haloprogin. authority. If clotrimazole is marketed This proposal does not apply to under the final monograph, the agency D. Response to Comment clotrimazole marketed OTC as an will monitor the quality of clotrimazole antifungal agent in intravaginal drug One comment (Ref. 12), submitted in products in the same manner as other products labeled for the treatment of response to the citizen petition (Ref. 1), products currently marketed under the vaginal yeast infections. The existing opposed monograph status for monograph. monograph for topical antifungal drug clotrimazole. The comment contended E. Labeling products does not contain any claims that safety, effectiveness, and for intravaginal use. therapeutic effect will not be assured Since 1989, antifungal drug products through the OTC drug monograph containing clotrimazole 1 percent have IV. References process because neither bioequivalence been marketed OTC in the United States The following references have been nor formulation changes will be with indications for the treatment of placed on display in the Dockets monitored by the agency. The comment athlete’s foot (tinea pedis), jock itch Management Branch (address above) argued that topical antifungal drug (tinea cruris), and ringworm (tinea and may be seen by interested persons products present interesting formulation corporis). The warnings and directions between 9 a.m. and 4 p.m., Monday and manufacturing issues and that the in the approved applications for these through Friday. agency could assure safety, products are very similar to those effectiveness, and interchangeability of contained in § 333.250(c) and (d) of the 1. Comment No. CP1, Docket No. 96P– clotrimazole products only through its final monograph for OTC antifungal 0460, Dockets Management Branch. 2. Comment No. SUP1, Docket No. 96P– application preapproval process. The drug products. If a manufacturer 0460, Dockets Management Branch. comment noted the Panel’s discussion chooses to market its clotrimazole 3. Comment No. LET3, Docket No. 96P– about vehicles for OTC topical product that is currently marketed OTC 0460, Dockets Management Branch. antifungal drug products (47 FR 12480 under an approved application under 4. Comment No. LET4, Docket No. 96P– at 12489 and 12490). The Panel the monograph in the future, it will 0460, Dockets Management Branch. discussed types and effects of different have to modify the product’s labeling to 5. Comment No. LET5, Docket No. 96P– vehicles, vehicle solubility and conform to the OTC drug monograph 0460, Dockets Management Branch. viscosity, and the rate of diffusion of an labeling in § 333.250. In either case, the 6. The United States Pharmacopeia 24–The antifungal drug from a vehicle. manufacturer will need to follow the National Formulary 19, The United States Pharmacopeial Convention, Inc., Rockville, The agency disagrees with the new OTC drug content and format comment. The agency does not consider MD, p. 451, 1999. labeling requirements in § 201.66 (21 7. Duhm, B. et al., ‘‘Pharmacokinetics of the inclusion of clotrimazole in the CFR 201.66). Topically Applied Bisphenyl-(2- topical antifungal drug products chlorophenyl) -1-imidazolyl-methane-[14C],’’ monograph at this time as any different III. The Agency’s Tentative Conclusions and Proposals Arzneittelforschung, 22:1289–191, 1972, than the previous inclusion of the English version, Drugs Made in Germany, former new drugs haloprogin and The agency has determined that 15:126–132, 1972. miconazole nitrate in the monograph. clotrimazole has been marketed to a 8. Clayton, Y. M. and B. L. Connor, Bioequivalence testing is not required material extent and for a material time ‘‘Comparison of Clotrimazole Cream, for either of those drugs currently as a topical antifungal drug and, based Whitfield’s Ointment and Nystatin Ointment marketed under the monograph. Based on the available data, can be generally for the Topical Treatment of Ringworm Infections, Pityriasis Versicolor, Erythrasma, on the previous monograph recognized as safe and effective for this and Candidiasis,’’ British Journal of determinations for haloprogin and use and included in the OTC drug Dermatology, 89:297–303, 1973. micinazole nitrate and the marketing of monograph for this class of products. 9. Fredriksson, T., ‘‘Topical Treatment clotrimazole OTC under NDA’s since Therefore, the agency is proposing to with Bay b 5097, A New Broad Spectrum 1989, the agency considers all three of add clotrimazole 1 percent as new Antimycotic Agent,’’ British Journal of these ingredients to have an extensive paragraph (g) in § 333.210. Dermatology, 86:628–630, 1972. history of safe and effective OTC use. The agency is allowing interim 10. Van Dersarl, J. V. and R. H. Sheppard, While formulation and manufacturing marketing of OTC topical antifungal ‘‘Clotrimazole vs. Haloprogin Treatment of issues for topical products may prevent drug products containing 1-percent Tinea Cruris,’’ Archives of Dermatology, clotrimazole with claims for the 113:1233–1235, 1977. FDA from allowing monograph status, 11. Weitgasser, H., ‘‘Clinical and Mycologic the agency has no evidence at this time treatment of athlete’s foot (tinea pedis), Trials with the Antifungal Medication to indicate that formulation and jock itch (tinea cruris), and ringworm Haloprogin,’’ Mykosen, 20:15–24, 1977. manufacturing issues have affected the (tinea corporis) to begin with the 12. Comment No. C1, Docket No. 96P– safety and effectiveness of clotrimazole. publication of this proposal to amend 0460, Dockets Management Branch. The Panel’s discussion about vehicles the monograph based on the OTC for these products was based on the marketing experience in the United V. Analysis of Impacts Panel’s general knowledge. Data on States since 1989 and because there are FDA has examined the impacts of this specific vehicles were not submitted to no labeling issues to be addressed at this proposed rule under Executive Order or reviewed by the Panel. No comments time. Such interim marketing is subject 12866, the Regulatory Flexibility Act (5
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U.S.C. 601–612) (as amended by subtitle $3,000 per stock keeping unit (SKU) Reduction Act of 1995 (44 U.S.C. 3501 D of the Small Business and Regulatory (individual products, packages, and et seq.). Rather, the existing monograph Fairness Act of 1996 (Public Law 104– sizes). Based on information in the labeling is a ‘‘public disclosure of 121)), and the Unfunded Mandates agency’s Drug Listing System, there are information originally supplied by the Reform Act of 1995 (Public Law 104–4) less than 10 manufacturers and Federal Government to the recipient for (2 U.S.C. 1501 et seq.). Executive Order distributors that together produce about the purpose of disclosure to the public’’ 12866 directs agencies to assess all costs 25 SKU’s of OTC topical antifungal drug (5 CFR 1320.3(c)(2)). and benefits of available regulatory products that contain clotrimazole. alternatives and, when regulation is Assuming that there are about 25 VII. Environmental Impact necessary, to select regulatory affected OTC SKU’s in the marketplace, The agency has determined under 21 approaches that maximize net benefits total one-time costs of relabeling would CFR 25.31(a) that this action is of a type (including potential economic, be $50,000 to $75,000 if the that does not individually or environmental, public health and safety, manufacturers of these products cumulatively have a significant effect on and other advantages; distributive changed their marketing from under an the human environment. Therefore, impacts; and equity). Under the approved application to under the OTC neither an environmental assessment Regulatory Flexibility Act, if a rule has drug monograph. In making this change, nor an environmental impact statement a significant economic impact on a these manufacturers would save money is required. substantial number of small entities, an by eliminating all costs associated with agency must analyze regulatory options maintaining an application. Likewise, VIII. Request for Comments that would minimize any significant other manufacturers who now wish to impact of the rule on small entities. market topical clotrimazole drug Interested persons may submit to the Section 202(a) of the Unfunded products will be able to enter the Dockets Management Branch (address Mandates Reform Act requires that marketplace without the costs above) written comments regarding the agencies prepare a written statement associated with an application. Their proposal by August 27, 2001. Written and economic analysis before proposing costs would involve the standard start- comments on the agency’s economic any rule that may result in an up costs of any OTC drug marketed impact determination may be submitted expenditure in any one year by State, under the monograph. on or before August 27, 2001. Three local, and tribal governments, in the The agency considered but rejected copies of all comments are to be aggregate, or by the private sector, of several alternatives: (1) Not including submitted, except that individuals may $100 million (adjusted annually for clotrimazole in the monograph, (2) a submit one copy. Comments are to be inflation). longer implementation period, and (3) identified with the docket number The agency believes that this no interim marketing. The agency found in brackets in the heading of this proposed rule is consistent with the rejected the first alternative because it document and may be accompanied by regulatory philosophy and principles considers the data presented supportive a supporting memorandum or brief. identified in the Executive Order. In of monograph status. The agency does Received comments may be seen in the addition, the proposed rule is not a not see a need for the second or third office above between 9 a.m. and 4 p.m., significant regulatory action as defined alternatives because these clotrimazole Monday through Friday. by the Executive Order, as explained drug products are already marketed IX. Proposed Effective Date below, and so is not subject to review OTC under approved applications and under the Executive Order. compendial standards currently exist for The agency is proposing that any final The purpose of this proposed rule is clotrimazole. The agency does not rule that may issue based on this to include clotrimazole 1 percent in the consider an exemption for small entities proposal become effective 30 days after monograph for OTC topical antifungal necessary because those manufacturers its date of publication in the Federal drug products. This proposal allows can enter the marketplace under the Register. current manufacturers of these products monograph at any time. to market their products under the OTC Under the Unfunded Mandates List of Subjects in 21 CFR Part 333 drug monograph instead of an NDA and Reform Act, FDA is not required to enables other manufacturers who wish prepare a statement of costs and benefits Labeling, Over-the-counter drugs. to market clotrimazole products OTC to for this proposed rule because this Therefore, under the Federal Food, enter the marketplace without having to proposed rule is not expected to result Drug, and Cosmetic Act and under obtain an NDA. In both cases, there will in any one-year expenditure that would authority delegated to the Commissioner be cost savings from marketing without exceed $100 million adjusted for of Food and Drugs, it is proposed that an NDA. inflation. 21 CFR part 333 be amended as follows: If current manufacturers of these This analysis shows that the agency products choose to market them under has considered the burden to small PART 333—TOPICAL ANTIMICROBIAL the OTC drug monograph, they should entities. Thus, this economic analysis, DRUG PRODUCTS FOR OVER-THE- incur only minor costs to relabel their together with other relevant sections of COUNTER HUMAN USE products to meet the monograph. Some this document, serves as the agency’s manufacturers may have to add a initial regulatory flexibility analysis, as 1. The authority citation for 21 CFR warning that was included in the final required under the Regulatory part 333 continues to read as follows: monograph, but not required when Flexibility Act. Authority: 21 U.S.C. 321, 351, 352, 353, some products containing clotrimazole 355, 360, 371. were approved for OTC marketing under VI. Paperwork Reduction Act of 1995 an NDA. These manufacturers can make FDA tentatively concludes that the 2. Section 333.210 is amended by this change whenever they are ready to labeling requirements for clotrimazole adding paragraph (g) to read as follows: order new product labeling. are not subject to review by the Office § 333.210 Antifungal active ingredients. Manufacturers have informed the of Management and Budget because agency that this type of relabeling cost they do not constitute a ‘‘collection of * * * * * generally averages about $2,000 to information’’ under the Paperwork (g) Clotrimazole 1 percent.
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Dated: May 17, 2001. Quality, P.O. Box 8468, 400 Market reasons. First, because it addresses the Margaret M. Dotzel, Street, Harrisburg, Pennsylvania 17105. requirements of the NOX SIP Call Phase Associate Commissioner for Policy. FOR FURTHER INFORMATION CONTACT: I, and secondly as a strengthening [FR Doc. 01–13299 Filed 5–25–01; 8:45 am] Cristina Fernandez, (215) 814–2178, or measure for the one-hour ozone BILLING CODE 4160–01–S by e-mail at [email protected]. standard attainment for Philadelphia- SUPPLEMENTARY INFORMATION: On Wilmington-Trenton ozone October 30, 2000 and April 4, 2001, the nonattainment area. ENVIRONMENTAL PROTECTION Pennsylvania Department of C. What Are the General NOX SIP Call AGENCY Environmental Protection (PADEP) Requirements? submitted a revision to the On October 27, 1998, EPA published 40 CFR Part 52 Pennsylvania SIP to address the a final rule entitled, ‘‘Finding of requirements of the NOX SIP Call Phase Significant Contribution and [PA 169—4116; FRL–6986–8] I. The information in this section is Rulemaking for Certain States in the organized as follows: Ozone Transport Assessment Group Approval and Promulgation of Air I. EPA’s Action Region for Purposes of Reducing Quality Implementation Plans; A. What action is EPA proposing today? Regional Transport of Ozone,’’ Pennsylvania; Nitrogen Oxides Budget otherwise known as the ‘‘NO SIP Call.’’ Trading Program B. Why is EPA proposing this action? X C. What are the general NOX SIP Call See 63 FR 57356. The NOX SIP Call AGENCY: Environmental Protection requirements? requires 22 States and the District of Agency (EPA). D. What is EPA’s NOX budget trading Columbia to meet statewide NOX program? emission budgets during the five month ACTION: Proposed rule. E. What guidance did EPA use to evaluate period between May 1 and October 1 in Pennsylvania’s submittal? SUMMARY: EPA is proposing to approve order to reduce the amount of ground a State Implementation Plan (SIP) II. Pennsylvania’s NOX Budget Trading level ozone that is transported across revision submitted by the Program the eastern United States. Commonwealth of Pennsylvania on A. When did Pennsylvania submit the SIP EPA determined state-wide NOX October 30, 2000 and April 4, 2001. revision to EPA in response to the NOX emission budgets for each affected This revision responds to the EPA’s SIP Call? jurisdiction to be met by the year 2007. regulation entitled, ‘‘Finding of B. What is the Pennsylvania NOX Budget EPA identified NOX emission Significant Contribution and Trading Program? reductions by source category that could C. What is the result of EPA’s evaluation of be achieved by using cost-effective Rulemaking for Certain States in the Pennsylvania’s program? Ozone Transport Assessment Group measures. The source categories Region for Purposes of Reducing III. Proposed Action included were electric generating units (EGUs), non-electric generating units Regional Transport of Ozone,’’ A. NOX SIP Call Requirements (non-EGUs), area sources, nonroad otherwise known as the ‘‘NOX SIP Call.’’ B. One-Hour Attainment Demonstration This revision establishes and requires a Plans mobile sources and highway sources. However, the NOX SIP Call allowed nitrogen oxides (NOX) allowance trading IV. Administrative Requirements program for large electric generating and states the flexibility to decide which industrial units, beginning in 2003. The I. EPA’s Action source categories to regulate in order to meet the statewide budgets. In the NO intended effect of this action is to A. What Action Is EPA Proposing X propose approval the Pennsylvania NO SIP Call notice, EPA suggested that X Today? imposing statewide NO emissions caps Budget Trading Program because it X EPA is proposing to approve the on large fossil-fuel fired industrial addresses the requirements of the NO X Pennsylvania SIP revision concerning boilers and electricity generating units SIP Call Phase I that will significantly the adoption of its NO Budget Trading would provide a highly cost effective reduce ozone transport in the eastern X Program, submitted on October 30, 2000 means for States to meet their NOX United States. EPA is proposing to and April 4, 2001. budgets. In fact, the state-specific approve this revision in accordance budgets were set assuming an emission with the requirements of the Clean Air B. Why Is EPA Proposing This Action? rate of 0.15 pounds NO per million Act. X EPA is proposing this action for two British thermal units (lb. NOX/mmBtu) DATES : Written comments must be purposes. Pennsylvania’s NOX Budget at EGUs, multiplied by the projected received on or before June 28, 2001. Trading Program regulations address the heat input (mmBtu) from burning the ADDRESSES: Written comments should requirements of the NOX SIP Call Phase quantity of fuel needed to meet the 2007 be mailed to David L. Arnold, Chief, Air I. In addition, Pennsylvania’s NOX forecast for electricity demand. See 63 Quality Planning and Information Budget Trading Program regulations are FR 57407. The calculation of the 2007 Services Branch, Mailcode 3AP21, U.S. part of the Pennsylvania one-hour ozone EGU emissions assumed that an Environmental Protection Agency, attainment demonstration plan for the emissions trading program would be Region III, 1650 Arch Street, Philadelphia-Wilmington-Trenton part of an EGU control program. The Philadelphia, Pennsylvania 19103. severe ozone nonattainment area. The NOX SIP Call state budgets also assumed Copies of the documents relevant to this Pennsylvania one-hour attainment on average a 30% NOX reduction from action are available for public demonstration plan for the cement kilns, a 60% reduction from inspection during normal business Philadelphia-Wilmington-Trenton industrial boilers and combustion hours at the Air Protection Division, ozone nonattainment area relies on the turbines, and a 90% reduction from U.S. Environmental Protection Agency, NOX reductions associated with the internal combustion engines. The non- Region III, 1650 Arch Street, NOX Budget Trading Program in 2003 EGU control assumptions were applied Philadelphia, Pennsylvania 19103; and and beyond. Therefore, EPA is at units where the heat input capacities Pennsylvania Department of proposing to approve Pennsylvania’s were greater than 250 mmBtu per hour, Environmental Protection, Bureau of Air NOX Budget Trading Program for two or in cases where heat input data were
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