[Federal Register Volume 59, Number 23 (Thursday, February 3, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-2263]


[[Page Unknown]]

[Federal Register: February 3, 1994]


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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



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21 CFR Part 351




Vaginal Drug Products for Over-the-Counter Human Use; Withdrawal of 
Advance Notice of Proposed Rulemaking
=======================================================================

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 351

 [Docket No. 82N-0291]
 RIN 0905-AA06

 
Vaginal Drug Products for Over-the-Counter Human Use; Withdrawal 
of Advance Notice of Proposed Rulemaking

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of withdrawal of advance notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is issuing a notice to 
withdraw the advance notice of proposed rulemaking of October 13, 1983 
(48 FR 46694) that would have established conditions under which over-
the-counter (OTC) vaginal drug products are generally recognized as 
safe and effective and not misbranded. FDA is issuing this notice of 
withdrawal after considering the report and recommendations of the 
Advisory Review Panel on OTC Contraceptives and Other Vaginal Drug 
Products (the Vaginal Panel) and public comments on an advance notice 
of proposed rulemaking that was based on those recommendations. This 
action is being taken in part because the agency has determined that 
some of the recommended labeling indications relate to cosmetic claims 
and not drug claims. In addition, recommended labeling indications and 
ingredients used for minor irritation, itching, or soreness are not 
unique to the vaginal area and are already being considered in other 
OTC drug rulemakings (e.g., antifungal, antimicrobial, and external 
analgesic). Therefore, those ingredients and indications will be 
considered in those other rulemakings, as appropriate.

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 October 13, 1983 
(48 FR 46694), FDA published, under Sec. 330.10(a)(6) (21 CFR 
330.10(a)(6)), an advance notice of proposed rulemaking to establish a 
monograph for OTC vaginal drug products, together with the 
recommendations of the Vaginal Panel, which was the advisory review 
panel responsible for evaluating data on the active ingredients in this 
drug class. Interested persons were invited to submit comments by 
January 11, 1984. Reply comments in response to comments filed in the 
initial comment period could be submitted by March 19, 1984.
     In accordance with Sec. 330.10(a)(10), the data and information 
considered by the Vaginal Panel were put on public display in the 
Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 
1-23, 12420 Parklawn Dr., Rockville, MD 20857, after deletion of a 
small amount of trade secret information.
     In this notice, FDA states for the first time its position on the 
establishment of a monograph for OTC vaginal drug products based on the 
Vaginal Panel's conclusions and recommendations on OTC vaginal drug 
products, the comments received, and the agency's independent 
evaluation of the Vaginal Panel's report. In the preamble to the 
advance notice of proposed rulemaking for OTC vaginal drug products (48 
FR 46694 at 46695), the agency expressed its concerns about: (1) The 
ability of a woman to recognize the nature or cause of the symptom(s) 
of vaginal itching, irritation, or soreness in order to determine which 
kind of drug product to select to treat the condition, and (2) whether 
1 to 2 weeks of self-medicating with an OTC drug product may pose an 
unacceptable delay in seeking professional attention if the symptom(s) 
of itching, irritation, or soreness are due to N. gonorrhoea, 
Trichomonas, Candida, or other organisms that will not be eradicated by 
topical therapy with nonantimicrobial OTC drug products. At that time, 
no final agency decisions were made regarding the Vaginal Panel's 
recommendations or the above stated concerns. The agency invited 
specific comments on these issues.
     In response to the advance notice of proposed rulemaking, four 
drug manufacturers, two trade associations, nine consumers, four 
medical associations, two pharmaceutical associations, three surgeons 
general, one poison control center, three consumer groups, two 
community health associations, and three practicing medical groups 
submitted comments. Copies of the comments received are on public 
display in the Dockets Management Branch (address above).
     All OTC volumes cited throughout this document refer to the 
submissions made by interested persons pursuant to the call-for-data 
notice published in the Federal Register of May 16, 1973 (38 FR 12840) 
or to additional information that has come to the agency's attention 
since publication of the advance notice of proposed rulemaking. The 
volumes are on public display in the Dockets Management Branch under 
docket number 82N-0291.

 I. The Agency's Tentative Conclusions on the Comments

 A. General Comments

     1. One comment contended that OTC drug monographs are 
interpretive, as opposed to substantive, regulations. The comment 
referred to statements on this issue submitted earlier to other OTC 
drug rulemaking proceedings.
     The agency addressed this issue in paragraphs 85 through 91 of the 
preamble to the procedures for classification of OTC drug products, 
published in the Federal Register of May 11, 1972 (37 FR 9464 at 9471 
to 9472), and in paragraph 3 of the preamble to the tentative final 
monograph for OTC antacid drug products, published in the Federal 
Register of November 12, 1973 (38 FR 31260). FDA reaffirms the 
conclusions stated in those documents. Court decisions have confirmed 
the agency's authority to issue substantive regulations by rulemaking. 
(See, e.g., National Nutritional Foods Association v. Weinberger, 512 
F.2d 688, 696-698 (2d Cir. 1975) and National Association of 
Pharmaceutical Manufacturers v. FDA, 487 F. Supp. 412 (S.D.N.Y. 1980), 
aff'd, 637 F.2d 887 (2d Cir. 1981).)
     2. One comment disagreed with the Vaginal Panel's statement that 
``If an active ingredient is present in a therapeutic concentration, 
the product is a drug, even if that product does not claim to produce 
the effect which will result from the action of the therapeutically 
effective ingredient * * *,'' (48 FR 46694 at 46701). The comment 
argued that drug status of a product is determined only by its intended 
use, not by the inclusion of certain ingredients, and the presence of a 
certain ingredient in a product offered solely as a cosmetic does not 
make the product a drug. The comment stated that FDA's policy 
concerning drug versus cosmetic status has been stated in many 
documents, including the procedural regulations governing the OTC drug 
review (37 FR 9464 to 9475), and that the Vaginal Panel did not 
properly apply this policy. The comment added that there is no 
justification to apply a different principle to this rulemaking for 
vaginal drug products. The comment requested that the term ``drug 
product'' be used throughout the regulation wherever products are 
specifically identified to emphasize the difference between cosmetic 
and drug products, e.g., vaginal douche drug products.
     The Federal Food, Drug, and Cosmetic Act (the act) provides the 
statutory definitions that differentiate a drug from a cosmetic. A 
``drug'' is defined in part as an article ``intended for use in the 
diagnosis, cure, mitigation, treatment, or prevention of disease'' or 
``intended to affect the structure or any function of the body * * *.'' 
(See 21 U.S.C. 321(g)(1)(B) and (C).) A ``cosmetic,'' on the other 
hand, is defined as an article intended to be ``* * * applied to the 
human body or any part thereof for cleansing, beautifying, promoting 
attractiveness, or altering the appearance, * * *.'' (See 21 U.S.C. 
321(i)(1).) Therefore, the agency agrees with the comment that the 
intended use of a product is the primary determining factor as to 
whether a product is a drug, a cosmetic, or both. This intended use may 
be inferred from the product's labeling, promotional material, 
advertising, and any other relevant factor. See, e.g., National 
Nutritional Foods Ass'n v. Mathews, 557 F.2d 325, 334 (2d Cir. 1977).
     The type and amount of ingredient(s) present in a product, even if 
that product does not make explicit drug claims, must be considered in 
determining its regulatory status. For example, the mere presence of a 
pharmacologically active ingredient could make a product a drug even in 
the absence of explicit drug claims. In these cases, the intended use 
would be implied because of the known or recognized drug effects of the 
ingredient (e.g., fluoride in a dentifrice).
     The agency does not believe that it is necessary to use the term 
``drug product'' throughout OTC drug monographs to distinguish between 
drug and cosmetic products because the labeling in final monographs 
applies only to products that fall within the statutory definition of a 
drug, and does not apply to cosmetic products. However, if a product is 
intended for both drug and cosmetic uses, e.g., cleansing and treating 
a disease condition, it must conform to the requirements of the 
applicable final monograph(s) for OTC drug products, as well as bear 
appropriate labeling for cosmetic use in conformity with section 602 of 
the act (21 U.S.C. 362) and the provisions of parts 701 and 740 (21 CFR 
parts 701 and 740).
     3. In response to the agency's specific request for comment on the 
appropriateness of OTC drug products for treating the symptoms of 
itching, irritation, and soreness in or around the vagina (48 FR 46694 
at 46695), several comments stated that treating these symptoms with 
OTC drug products is appropriate and rational therapy because women can 
readily recognize these symptoms and the benefits to be derived from 
the use of these drugs far outweigh any risks associated with their OTC 
availability. A number of comments stated that there is no valid 
medical basis to conclude, as was suggested by FDA in the preamble of 
the advance notice of proposed rulemaking for OTC topical antifungal 
drug products (47 FR 12480, March 23, 1982), that a serious health 
hazard could result from self-treating the symptom of external feminine 
itching. The comments contended that the likelihood of masking more 
serious gynecological disorders such as gonorrhea or trichomoniasis, or 
masking a more serious condition such as diabetes, was highly unlikely 
provided the labeling of the products advises consumers to consult a 
physician if symptoms worsen or persist for longer than 1 week. To 
further support its contention that serious complications or delays in 
proper medical diagnosis are not likely to occur if the symptoms of 
external vaginal itching are treated with OTC drug products, one 
comment cited the safe marketing experience of OTC hydrocortisone 
products labeled with an indication that included ``external genital 
(feminine) itching.'' The comment stated that none of the possible 
problems projected, i.e., the masking of serious disease, the inability 
to self-diagnose, and the presumed side effects of the drug, had 
materialized since the marketing of OTC hydrocortisone began in 1979. 
Several comments also argued that external vaginal itching and 
irritation are not necessarily caused by infection, but can often be 
caused by irritating clothing, sensitivities to cosmetics, 
inappropriate hygiene, or other external factors.
     In contrast, several comments stated that women should never self-
treat the symptoms of vaginal itching, irritation, or soreness because 
they are not capable of self-diagnosis (i.e., specifically determining 
an appropriate drug product to use based on various vaginal symptoms) 
and should always be evaluated by a physician. The comments added that 
self-treatment could unreasonably delay a proper diagnosis and could 
even complicate it.
     The agency notes that all of the products submitted to the Vaginal 
Panel were intended for intravaginal use and with the exception of 
vaginal contraceptives, the use of these OTC vaginal products, e.g., 
douches, suppositories, had been for the most part limited to cosmetic 
purposes, e.g., cleansing, deodorizing, mechanical flushing. Thus, the 
agency concludes that with the exception of indications relating to 
minor itching, irritation, and soreness, all other recommended vaginal 
monograph indications listed in the Vaginal Panel's report (48 FR 46694 
at 46729) are cosmetic in nature or outside the scope of the OTC drug 
review, e.g., ``Astringent,'' ``Removes vaginal discharge,'' ``Removes 
vaginal secretions,'' ``Mild detergent action.'' Such indications for 
vaginal products refer to a product's transitory cleansing effects 
rather than to claimed therapeutic effects. (See drug/cosmetic 
discussion in comment 2.) Therefore, except for some ``astringent'' 
claims (see comment 13), the agency considers these indications outside 
the scope of the OTC drug review. The agency has no objection to the 
continued availability of vaginal products bearing labeling claims 
related to cleansing for cosmetic purposes, but does not believe that 
these cosmetic products should be labeled or used for therapeutic 
purposes except under the advice and supervision of a physician. As a 
result of this withdrawal notice, manufacturers may need to relabel or 
reformulate some products now or in the future. However, if 
reformulation and/or relabeling are necessary, the cost will be minimal 
because reformulation and relabeling will be required, in any event, 
under other appropriate rulemakings.
     The agency believes that consumers should have access to OTC drug 
products to provide temporary relief of vaginal itching and irritation. 
The agency recognizes that the safe marketing experience of 
hydrocortisone, which has been available OTC since 1979 with an 
indication that includes use on itchy anal and genital areas, provides 
support that serious complications or delays in proper medical 
diagnosis are not likely to occur if the symptom of vaginal itching is 
treated with OTC drug products. Therefore, based on the available data 
and information, the agency believes that the relief of vaginal 
symptoms such as itching and irritation is an acceptable labeling claim 
for certain OTC drug products.
     As stated above, all of the products submitted to the Vaginal 
Panel were intended for intravaginal use and concerns arose about self-
diagnosis, selection of an appropriate drug product, and self-treatment 
of intravaginal disorders. The Fertility and Maternal Health Drugs 
Advisory Committee (the Committee), in a meeting held June 14 and 15, 
1990, discussed the proposal that vaginal fungicides be sold OTC for 
the treatment of yeast (Candida) infections. Although a mechanism for 
initial self-diagnosis was not considered, the Committee believed that 
consumers could safely and adequately recognize and treat subsequent 
intravaginal yeast infections after an initial diagnosis had been made 
by a physician and recommended that vaginal antifungal drug products 
whose safety was well-established be made available OTC with 
appropriate labeling (Ref. 1). Based on the Committee's recommendations 
and other available data, the agency has determined that certain OTC 
drug products for intravaginal use to treat yeast infections or for the 
relief of minor irritation, itching, and soreness can be safely used 
OTC. However, as recommended above, the agency believes that antifungal 
or other drug product ingredients for OTC intravaginal use are 
appropriate only for those women who have previously been diagnosed by 
a physician as having had the condition for which these drug products 
are intended and are therefore able to subsequently recognize the 
symptoms of the condition. The agency intends to discuss proposed 
labeling and specific ingredients for OTC intravaginal use in an 
amendment to the final monograph for OTC antifungal drug products in a 
future issue of the Federal Register.
     While a number of ingredients in OTC drug products could be used 
in and around the vagina to relieve symptoms such as itching, 
irritation, or soreness, the use of these ingredients is not specific 
or unique to the vaginal area; i.e., they could be used topically to 
relieve these same symptoms elsewhere on the body. For example, 
antifungals, antipruritics, skin protectants, and astringents all have 
potential for relieving symptoms occurring externally around the vagina 
as well as on other parts of the body. It should be noted, however, 
that certain drug product classes, e.g., antifungals, may be capable of 
relieving itching and irritation by means of killing the cause of the 
itch (e.g., yeast/fungus). These products would not be expected to be 
routinely effective in treating ``itch'' due to other causes, e.g., 
poison ivy, eczema, insect bites, etc.
    Also, in other OTC drug rulemakings, the agency has included, where 
appropriate, the various conditions for which an ingredient is 
considered generally recognized as safe and effective for OTC use in 
one monograph. (See, for example, the discussion on hydrocortisone for 
use in psoriasis (51 FR 27346 at 27360) and the discussion on menstrual 
claims for internal analgesics (53 FR 46204 at 46209).) Therefore, for 
those ingredients that are considered safe and effective for use in 
relieving conditions in and around the vagina, the agency believes it 
is more appropriate to include a vaginal claim in the applicable OTC 
drug monograph rather than to have a separate monograph for ingredients 
and claims related to vaginal use only. (See, for example, ``external 
feminine itching'' claims for hydrocortisone products included in the 
tentative final monograph for OTC external analgesic drug products (48 
FR 5852 at 5868).)
     Therefore, based on the discussion above, the agency is 
withdrawing the advance notice of proposed rulemaking for OTC vaginal 
drug products, which indicated the intention to create new subpart B of 
proposed part 351. This withdrawal reflects the agency's intention 
regarding the language previously published for potential codification 
in part 351, but does not negate or reject the advisory panel's report. 
Specific vaginal claims for the various pharmacologic classes of 
ingredients will be considered in other appropriate monographs. Because 
the issues raised by the comments may significantly affect these other 
OTC drug rulemakings, the agency believes it is useful to respond to 
these issues in this document. These issues and the agency's response 
to them will also be discussed in other appropriate OTC drug 
rulemakings. Interested persons may, at that time, submit comments to 
the applicable rulemakings.

 Reference

     (1) Summary Minutes of the Fertility and Maternal Health Drugs 
Advisory Committee, dated June 14-15, 1990, in OTC Vol. 11BTFM.
     4. Several comments supported the recommendations of the Advisory 
Review Panel on OTC Antimicrobial II Drug Products (the Antimicrobial 
II Panel) that proposed a prescription to OTC switch of certain topical 
antifungal drugs for treating external feminine itching associated with 
a yeast infection (47 FR 12480). These comments stressed that candidal 
(yeast) infections of the vagina are extremely common and recurrent and 
that women can recognize with reasonable certainty when they have a 
yeast infection, especially if they have had one before.
     The agency is aware that all three OTC advisory review panels 
charged with reviewing products that could be used in or around the 
vagina concluded that vaginal infections could not be self-diagnosed or 
self-treated. The panels' conclusions are consistent with FDA policy 
that infections in general should not be self-diagnosed by consumers or 
self-treated with OTC drug products. The only exception to this general 
policy is the OTC use of topical antifungals for treating athlete's 
foot, jock itch, and ringworm. The Antimicrobial II Panel that reviewed 
topical antifungal drug products and FDA have determined that these 
infections are so common and recurrent that they are amenable to self-
diagnosis and treatment. In addition, the Antimicrobial II Panel 
recommended that haloprogin, miconazole, and nystatin be switched from 
prescription to OTC status for external feminine itching associated 
with a yeast infection. The Antimicrobial II Panel did not recommend 
these ingredients for treatment of the infection itself, but believed 
that OTC availability of these ingredients would be beneficial in 
providing rapid symptomatic relief of itching. The issue of consumer 
diagnosis of recurrent infections after appropriate physician diagnosis 
of the initial infection was not discussed during any of the panels' 
consideration of this issue.
     The Antimicrobial II Panel also recommended that haloprogin, 
miconazole, and nystatin be available OTC for the treatment of 
superficial skin infections caused by yeast (Candida) (47 FR 12480 at 
12565) However, the agency concluded in the tentative final monograph 
for OTC antifungal drug products (54 FR 51136 at 51140) that no 
antifungal ingredient should be labeled for OTC use for the treatment 
of cutaneous candidiasis. However, the agency stated that cutaneous 
candidiasis claims for effective antifungal ingredients could 
appropriately be included in professional labeling. As stated in 
comment 3, in light of the recommendations of the Committee, the agency 
has reevaluated its position on the availability of antifungal drug 
products for OTC treatment of vaginal yeast (Candida) infections. The 
antifungal ingredients clotrimazole and miconazole nitrate, at specific 
concentrations, have been approved for OTC intravaginal use, for 
specific indications, under new drug applications (Refs. 1 and 2).

References

     (1) Labeling from NDA 18-052 for Gyne-Lotrimin Vaginal Cream, 
in OTC Vol. 11BTFM, Docket No. 82N-0291, Dockets Management Branch.
     (2) Labeling from NDA 17-450 for Monistat 7 Vaginal Cream, in 
OTC Vol. 11BTFM, Docket No. 82N-0291, Dockets Management Branch.
     5. One comment disagreed with the Vaginal Panel's recommendation 
that ingredients classified as Category II for use in OTC vaginal drug 
products be removed automatically from vaginal cosmetic products (48 FR 
46694 at 46710). The comment stated that this action is unwarranted 
because the safety of cosmetic ingredients is assured by the 
manufacturers, who consider not only the scientific analyses done by 
the OTC advisory panels and FDA, but also additional published and 
unpublished data that may not have been reviewed by the panels. The 
comment also contended that the specific use of an ingredient in a 
cosmetic may differ from its use in a drug product.
     The agency notes that the Vaginal Panel made this recommendation 
in discussing Category II combination vaginal drug products. The 
Vaginal Panel recommended to the agency that any Category II ingredient 
that causes a combination product to be placed in Category II for 
safety reasons be removed from products regardless of whether they are 
intended for use as a drug or a cosmetic because of concerns about 
protecting consumers from unsafe ingredients. While sharing the Vaginal 
Panel's concern, the agency agrees with the comment that automatic 
removal of Category II drug ingredients from cosmetic products is not 
warranted because other factors need to be considered. For example, 
while an ingredient may not be safe in one concentration for use as a 
drug, it may be acceptable for use at a lower concentration in a 
cosmetic product. However, the agency will look carefully at any 
ingredients that are present in cosmetic products when those 
ingredients have been found unsafe for use in OTC drug products. FDA is 
prepared to take appropriate regulatory action in preventing the use of 
ingredients in cosmetic products when a potential health hazard is 
known to exist with their continued use. (See 21 CFR part 700--subpart 
B.)
     6. One comment stated that the Vaginal Panel ``may have 
inappropriately suggested the need for effectiveness testing for 
vaginal drug product final formulations'' (48 FR 46694 at 46724 and 
46725). The comment stressed that the OTC drug review is intended to be 
an active ingredient review and that testing is not necessary for final 
formulations of these products.
     In discussing testing guidelines for vaginal douche products, the 
Vaginal Panel simply stated that it did not require effectiveness 
testing for douches that make only cosmetic claims, e.g., 
``cleansing.'' However, the Vaginal Panel recommended that 
effectiveness testing should be required for those ingredients in 
vaginal douches that make drug claims, e.g., ``relieving irritation.''
     As discussed in comment 3, the agency is withdrawing the advance 
notice of proposed rulemaking for OTC vaginal drug products and is 
referring consideration of specific claims and ingredients for use in 
and around the vagina to other appropriate OTC drug rulemakings. Any 
necessary final formulation testing will also be discussed in those 
rulemakings, e.g., ingredients used in vaginal antiseptic drug 
products.

 B. Comments on Active Ingredients

     7. Two comments objected to the Vaginal Panel's conclusion that 
data are insufficient to prove the safety of quaternary ammonium 
compounds (i.e., benzalkonium chloride, benzethonium chloride, and 
methylbenzethonium chloride) for vaginal use (48 FR 46694 at 46717). 
The comments stated that although the Vaginal Panel's concern was based 
on published literature reports where the use of these compounds was 
associated with infections caused by Pseudomonas, it was not 
scientifically sound to use these reports to conclude that a safety 
problem exists. The comments mentioned that the Vaginal Panel failed to 
state that these reports resulted from the contamination of solutions 
that were employed in laboratory and hospital settings to sterilize 
medical devices used in urinary and cardiac catheterization or 
cystoscopic or related invasive procedures. Such procedures are usually 
conducted on patients whose normal body defenses have been compromised. 
Because Pseudomonas infections occur primarily in debilitated patients 
and Pseudomonas does not cause vulvovaginitis, the comments stated that 
it is scientifically inappropriate to cite these reports and through 
extrapolation conclude that the use of quaternary ammonium compounds in 
vaginal drug products presents a health hazard to normal individuals.
     The comments cited several references (Refs. 1 through 7) to show 
that the Vaginal Panel's concerns with respect to vaginal contamination 
by Pseudomonas in the presence of quaternary ammonium compounds are not 
supported by the weight of scientific data. The comments added that 
extensive toxicological studies on these compounds have been published 
(Ref. 8). The comments requested the agency to affirm the safety of 
quaternary ammonium compounds and classify them as Category I for use 
in relieving minor irritations of the vagina.
     Another comment stated that quaternary ammonium compounds 
historically have been included in vaginal products as preservatives 
and that these ingredients should be allowed to continue to be used for 
this purpose.
     The agency agrees with the comments' reasoning that the reports 
cited by the Vaginal Panel about Pseudomonas infections are not 
adequate to conclude that the use of quaternary ammonium compounds in 
OTC vaginal drug products may present a health hazard to normal 
individuals. The agency has no objection to the continued use of 
quaternary ammonium compounds as preservatives in OTC drug and cosmetic 
products provided the products are manufactured in accordance with 
established procedures that assure the adequacy of preservative systems 
and microbial limits of products.
     With respect to the use of quaternary ammonium compounds as active 
ingredients in OTC vaginal drug products for relieving symptoms of 
itching, irritation, or soreness, the Vaginal Panel stated that it was 
unaware of any data that demonstrated effectiveness for these uses (48 
FR 46694 at 46718). The comments did not include any new data, and the 
agency is unaware of any such data.
     As explained in comment 3, the agency has decided to consider 
specific vaginal claims for the various ingredients in other 
appropriate rulemakings. Quaternary ammonium compounds are included as 
Category I ingredients in the tentative final monograph for OTC first 
aid antiseptic drug products, published in the Federal Register of July 
22, 1991 (56 FR 33644). Any comments or new data received regarding 
specific vaginal use of quaternary ammonium compounds will be 
considered by the agency in the rulemaking for OTC topical 
antimicrobial drug products.

References

     (1) Forkner, Jr., C. E., ``Pseudomonas aeruginosa Infections,'' 
in ``Modern Medical Monographs,'' vol. 22, edited by I. S. Wright 
and R. H. Orr, Gruen and Stratton, New York, pp. 71-73, 1960.
     (2) Gardner, H. L., and R. H. Kaufman, ``Nonvenereal Bacterial 
Vulvovaginitides,'' in ``Benign Diseases of the Vulva and Vagina,'' 
C. V. Mosby Co., St. Louis, p. 212, 1969.
     (3) Charles, D., ``Major Problems in Obstetrics and 
Gynecology,'' W. D. Saunders Co., pp. 4-5, 1980.
     (4) Pidieu, C. M., ``The Vulva, Major Problems in 
Dermatology,'' vol. 5, edited by A. Rook, W. B. Saunders Co., 
Philadelphia, p. 99, 1979.
     (5) Monif, G. R. F., ``Infectious Disease in Obstetrics and 
Gynecology,'' 2d edition, Harper and Row, Hagerstown, MD, pp. 524-
525, 1982.
     (6) Mead, P. B., and D. W. Gump, ``Antibiotic Therapy In 
Obstetrics and Gynecology,'' in ``Clinical Obstetrics and 
Gynecology,'' edited by H. J. Osofsky and G. Schaefer, Harper and 
Row, Hagerstown, MD, pp. 109-129, 1976.
     (7) Gardner, A. et. al., ``Long Term Multicenter Trial with Ta-
Ro-Cap, A New Spermicidal Product,'' Contraception, 20:489-495, 
1979.
     (8) Finnegan, J. K., and J. B. Dienna, ``Toxicity of 
Quaternaries,'' Soap and Sanitary Chemicals, February 1954.
     8. One comment supported the Vaginal Panel's Category I 
classification of potassium sorbate (48 FR 46694 at 46704) and 
disagreed with the agency's conclusion that potassium sorbate is a new 
drug because it has not been marketed as a drug to a material extent 
and for a material time in the United States (48 FR 46694 at 46695). 
The comment stated that a product containing potassium sorbate had been 
marketed for over 2 years and that this ingredient is generally 
recognized as safe and effective for the treatment of minor vaginal 
itching and irritation and should be included as a monograph 
ingredient. The comment contended that potassium sorbate is safe 
because it was so recognized by the Vaginal Panel, and because of the 
lack of ``any report of major side effects, adverse reaction or 
complaint'' while 14 million units of a product containing this 
ingredient were sold for over 2 years before marketing was 
discontinued. The comment argued that potassium sorbate is effective 
because it was so recognized by the Vaginal Panel based on two adequate 
and well-controlled clinical studies (48 FR 46694 at 46704). The 
comment added that this ingredient has been historically used by 
physicians for treatment of vaginal itching and irritation, and that 
this professional use constitutes use ``for a material time and to a 
material extent.'' The comment also argued that potassium sorbate is 
safer than povidone-iodine, which the Vaginal Panel recommended as a 
Category I ingredient for these uses. The comment concluded that 
potassium sorbate is not a new drug because of its historical use and 
because of its marketing history, and should be placed in Category I as 
a monograph ingredient.
     In the preamble to the Vaginal Panel's report (48 FR 46694 at 
46695), the agency stated its opinion as follows:
     The agency is not aware of the marketing of any drug product 
containing potassium sorbate as an active ingredient prior to 
adoption of the Panel's report, although at least one product has 
entered the marketplace since that time. Because potassium sorbate 
has not been marketed as a drug to a material extent and for a 
material time in the United States, the agency considers this 
ingredient to be a new drug within the meaning of section 201(p) of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321(p)). It may 
not be marketed until FDA has approved a new drug application (NDA) 
for such use.
     The agency has not at this time changed its position on potassium 
sorbate for the treatment of minor vaginal itching and irritation. 
However, issues about the agency's interpretations regarding marketing 
to a ``material extent'' and for a ``material time'' as threshold 
criteria for inclusion of an ingredient in the OTC drug review have 
been raised in a number of rulemakings. Citizen petitions (Refs. 1 and 
2) have been filed requesting the agency to change its longstanding 
position on these threshold criteria, especially with regard to 
permitting foreign marketing to satisfy the material time and extent 
criteria. The agency intends to address the material time and extent 
issues in a consolidated response in a future issue of the Federal 
Register.

References

     (1) Comments No. CP2, CP3, and CP4 Docket No. 78N-0038, Dockets 
Management Branch.
     (2) Comment No. CP1, Docket No. 92P-0309, Dockets Management 
Branch.
     9. One comment requested that Category I approval of povidone-
iodine as an active ingredient for the relief of minor irritations of 
the vagina be extended to include a vaginal suppository as well as a 
douche dosage form. The comment stated that the absorption potential 
with a suppository dosage form should be no greater than with a vaginal 
douche, and that there is no basis for making a distinction between a 
suppository and a douche dosage form with respect to effectiveness.
     In response to a comment comparing the relative safety of 
potassium sorbate to povidone-iodine (see comment 8), one comment 
contended that the safety and effectiveness questions raised by the 
other comment with respect to povidone-iodine were superficial and 
erroneous and were in disregard of the facts. The comment stated that 
over 1,000 published studies and over 30 years of experience 
demonstrate the safety and effectiveness of povidone-iodine and confirm 
its Category I status for vaginal use as a douche.
     Povidone-iodine in various formulations for vaginal use, i.e., 
douche and gel, was originally reviewed under the FDA Drug Efficacy 
Study Implementation (DESI). The DESI panel concluded that povidone-
iodine was effective as a douche, i.e., for cleansing purposes, and 
that povidone-iodine could offer some partial or temporary relief of 
itching and odor when infection was present. Only the douche 
formulation was deferred for consideration to the OTC drug review. In 
the Federal Register of October 13, 1983 (48 FR 46694 at 46705), the 
Vaginal Panel reviewed the povidone-iodine douche product (0.15 to 3 
percent) and placed it in Category I for the relief of minor 
irritations of the vagina. The Vaginal Panel did not review povidone-
iodine in a suppository dosage form because no data on this dosage form 
were submitted. However, the Vaginal Panel did consider the suppository 
dosage form for claims relating to relief of minor irritation, and 
reduction of number of pathogenic microorganisms, and stated that such 
claims must be substantiated by testing (48 FR 46694 at 46702). The 
safety and effectiveness of povidone-iodine for the relief of itching 
and minor irritation in and around the vagina will be discussed by the 
agency in the rulemaking for OTC topical antimicrobial drug products in 
a future issue of the Federal Register. (See also discussion in comment 
17 regarding professional labeling claims.)

 C. Comments on Labeling

     10. One comment objected to the Vaginal Panel's recommendation 
that OTC drugs be labeled with the components of perfumes that are 
included in the products. The comment explained that fragrances and 
flavors are often made up of dozens of ingredients and that to list 
each of these individually would be a practical impossibility; 
furthermore, the composition of a perfume is a significant trade 
secret. The comment pointed out that this issue had been considered and 
rejected by Congress and FDA on several occasions over the past decade, 
and concluded that there was no reason whatsoever to change these 
previous decisions.
     Because section 502(e) of the act (21 U.S.C. 352(e)) specifies the 
requirements for the labeling of active and inactive ingredients in 
drug products, there is no need to include such requirements in an OTC 
drug monograph. However, the agency notes that although section 502(e) 
of the act does not require the complete identification of all inactive 
ingredients in the labeling of OTC drugs, it does require the 
disclosure of certain ingredients, whether included as active or 
inactive components in a drug product. Although FDA does not require 
the inclusion of all the inactive ingredients in OTC drug product 
labeling, the agency urges manufacturers to list all inactive 
ingredients voluntarily as recommended by the Vaginal Panel. This 
information will enable the consumer with known allergies or 
intolerance to certain ingredients to select products with increased 
confidence of safe use.
     After the Vaginal Panel made its recommendations to FDA, the 
Nonprescription Drug Manufacturers Association (NDMA) (formerly the 
Proprietary Association), the trade association that represents OTC 
drug manufacturers who reportedly market 90 to 95 percent of all OTC 
drug products sold in the United States, implemented a program under 
which its member companies voluntarily list inactive ingredients in the 
labeling of OTC drug products under guidelines established by NDMA 
(Ref. 1). Although these guidelines do not specify the listing of each 
ingredient contained in the fragrance or perfume in the product, they 
do provide for such inactive ingredients as flavors and fragrances to 
be listed as ``flavors'' and ``fragrances.'' Hence, the consumer with 
known allergies or intolerances to such inactive ingredients as 
flavors, fragrances, or perfumes would be generally aware of their 
inclusion in certain OTC drug products. The agency commends these 
voluntary efforts and urges all OTC drug manufacturers to label their 
products voluntarily in accordance with NDMA's guidelines.

 Reference

     (1) ``Proprietary Association Adopts Voluntary Disclosure of 
Inactive Ingredients,'' news release, The Proprietary Association, 
Washington, May 14, 1984, copy included in OTC Vol. 11BTFM, Docket 
No. 82N-0291, Dockets Management Branch.
     11. Several comments argued that FDA cannot legally and should 
not, as a matter of policy, prescribe exclusive lists of terms from 
which statements of identity and indications for use of OTC drug 
products must be drawn and prohibit alternative OTC labeling 
terminology which is truthful, not misleading, and intelligible to the 
consumer to describe such indications. Two comments argued that such a 
restriction is an unconstitutional restriction of commercial speech and 
exceeds FDA's authority. One comment stated that this ``exclusivity 
policy'' is not warranted as a matter of sound public policy, and 
recommended that FDA follow a guideline labeling policy instead of an 
exclusive one. One comment objected that the advance notice of proposed 
rulemaking was more restrictive in limiting the ``statements of 
identity'' than is the regulation in Sec. 201.61 (21 CFR 201.61). The 
comment urged the agency to allow manufacturers the alternative ways of 
describing the statements of identity that are allowed in Sec. 201.61.
     In the Federal Register of May 1, 1986 (51 FR 16258), the agency 
published a final rule changing its labeling policy for stating the 
indications for use of OTC drug products. Under Sec. 330.1(c)(2) (21 
CFR 330.1(c)(2)), the label and labeling of OTC drug products are 
required to contain in a prominent and conspicuous location, either: 
(1) The specific wording on indications for use established under an 
OTC drug monograph, which may appear within a boxed area designated 
``APPROVED USES''; (2) other wording describing such indications for 
use that meets the statutory prohibitions against false or misleading 
labeling, which shall neither appear within a boxed area nor be 
designated ``APPROVED USES''; or (3) the approved monograph language on 
indications, which may appear within a boxed area designated ``APPROVED 
USES,'' plus alternative language describing indications for use that 
is not false or misleading, which shall appear elsewhere in the 
labeling. All other OTC drug labeling required by a monograph or other 
regulation (e.g., statement of identity, warnings, and directions) must 
appear in the specific wording established under the OTC drug monograph 
or other regulation where exact language has been established and 
identified by quotation marks, e.g., Secs. 201.63 or 330.1(g).
     12. One comment stated that FDA's exclusivity policy is a drug 
labeling policy that has no application to cosmetic claims appearing in 
the labeling of products that are both cosmetics and drugs.
     The agency agrees with the comment that the labeling restrictions 
in OTC drug monographs apply only to products that fall within the 
statutory definition of ``drugs'' and not to cosmetic products. This 
distinction between drugs and cosmetics is discussed in comment 3.
     Final OTC drug monographs cover only the drug use of the active 
ingredients listed therein. The concentration range, limitations, 
statements of identity, indications, warnings, and directions 
established for these ingredients in a monograph do not apply to the 
use of the same ingredients in products intended solely as cosmetics. 
However, if a product is intended for both drug and cosmetic use, it 
must conform to the requirements of the applicable final monograph(s). 
In addition to any indications allowed for OTC drug products bearing 
claims for vaginal use, such products may also bear appropriate 
labeling for cosmetic use(s), in conformity with section 602 of the act 
and the provisions of parts 701 and 740. In accordance with the final 
rule on the agency's exclusivity policy (51 FR 16258, May 1, 1986), 
cosmetic claims may not appear within the boxed area designated 
``APPROVED USES.'' As discussed at 51 FR 16258 at 16264 (paragraph 14), 
cosmetic claims may appear elsewhere in the labeling but not in the box 
should manufacturers choose the labeling alternative provided in 
Sec. 330.1(c)(2)(i) or (c)(2)(iii) for labeling cosmetic drug products.
     13. One comment agreed with the Vaginal Panel's conclusions that 
the terms ``cleansing,'' ``producing soothing and refreshing effects,'' 
and ``deodorizing'' (as used in the definitions of vaginal douche and 
vaginal suppository) are cosmetic claims (48 FR 46694 at 46701). The 
comment urged the agency to accept the Vaginal Panel's recommendation. 
In addition to the claims above, another comment also considered the 
claim ``producing an astringent effect'' to be a cosmetic claim. The 
comment argued that these claims do not make a vaginal product into a 
drug, that it is legally inappropriate to include them in the 
definitions of these products in proposed Sec. 351.103 of the 
monograph, and that they should be removed from the definitions section 
and anywhere else they appear in the document.
     The agency agrees that cosmetic claims should not be included in 
OTC drug rulemakings. Therefore, the cosmetic claims ``cleansing,'' 
``soothing,'' ``refreshing,'' and ``deodorizing'' will not be included 
in OTC drug monographs. The agency believes, however, that astringency 
can be either a drug claim or a cosmetic claim, depending on the 
intended use and labeling of the product. For example, astringent 
products intended and labeled for the relief of minor vaginal 
irritation or reduction in local edema would be considered as drugs, 
while astringent products intended and labeled for a refreshing effect 
would be considered as cosmetics. A product making both claims would be 
both a drug and a cosmetic. Thus, the agency will consider the intended 
use in determining whether it is a cosmetic, a drug, or both (see also 
comment 3).
     14. One comment stated that the Vaginal Panel's categorization of 
cosmetic claims as Category II drug claims is inappropriate because 
cosmetic claims are not within the jurisdiction of the OTC drug review. 
The comment contended that the following claims were inappropriately 
classified as Category II drug claims by the Vaginal Panel (48 FR 46694 
at 46710) because these claims are really cosmetic claims:
 Effectively cleanses
Effectively deodorizes
Cleans thoroughly
Destroys odor
Continued vaginal cleanliness
Cleanses more thoroughly than other douches
Removes contraceptive jellies and creams
Changes water into a cleansing solution
Complete feminine hygiene
Personal hygiene
Hypoallergenic
Feminine hygiene
Intimate cleanliness
Prevents disagreeable odors
Effective germ killer
Routine feminine hygiene
Completely refreshed
     The comment also contended that the Vaginal Panel placed the 
following ``other product quality claims'' in Category II and that 
these claims do not belong in the rulemaking because they are not drug 
claims:
Fortified triple strength
Scientifically balanced formula
Intimately understood
Changes water into a cleansing solution
Naturally safe ingredients
Formula like the natural environment in
    your body
Ph of 3.5
Effective liquid
Nonacid
Intended for all women who want to enjoy extra confidence in meeting 
people
As with all vaginal douches, its function is not to cover up odor
 Unlike spray deodorants which offer less protection
Complete feminine daintiness
Clinically tested
Dainty and feminine
Gentle
Safe for delicate membranes
Contains only the mildest ingredients
 Completely compatible with normal vaginal environment
Buffered to control a normal vaginal pH
     Stating that the Vaginal Panel did not provide a reason for its 
recommendation, the comment requested that reference to these claims be 
deleted at the next stage of the rulemaking.
     Although there will not be another stage in this rulemaking, the 
comment's concerns regarding these label terms are relevant to vaginal 
claims for OTC drug products subject to other OTC drug monographs. 
Therefore, the agency believes it is pertinent to address the comment's 
concerns.
     The OTC drug review establishes conditions under which some OTC 
drugs are generally recognized as safe and effective and not 
misbranded. Two principal conditions examined during the review are 
allowable ingredients and allowable labeling. FDA has determined that 
it is not practical--in terms of time, resources, and other 
considerations--to set standards for all labeling found in OTC drug 
products. Accordingly, OTC drug monographs regulate only labeling 
related in a significant way to the safe and effective use of covered 
products by lay persons. OTC drug monographs establish allowable 
labeling for the following items: product statement of identity; names 
of active ingredients; indications for use; directions for use; 
warnings against unsafe use, side effects, and adverse reactions; and 
claims concerning mechanism of drug action. The agency agrees with the 
comment that some of the claims listed above are either solely cosmetic 
claims or do not relate in a significant way to the safe and effective 
use of OTC vaginal drug products and, therefore, are outside the scope 
of the OTC drug review. Although these terms are considered outside the 
scope of the review, if used in the labeling of OTC drug products they 
will be evaluated by the agency on a product-by-product basis, under 
the provision of section 502 of the act relating to labeling that is 
false or misleading. Moreover, any term that is outside the scope of 
the review, even though it is truthful and not misleading, may not 
appear in any portion of the labeling required by a monograph and may 
not detract from such required information. However, terms outside the 
scope of a monograph may be included elsewhere in the labeling, 
provided they are not false or misleading. In addition, as explained in 
comment 2, the labeling restrictions in final monographs apply only to 
products that fall within the statutory definition of a drug, and not 
to cosmetic products. However, if a product is intended for both drug 
and cosmetic use, it must conform not only to the requirements of the 
applicable final monographs, but also to section 602 of the act and the 
regulations in parts 701 and 740.
     15. One comment contended that the use of the adjective 
``vaginal'' modifying ``douche'' in the statement of identity in 
Sec. 351.152(a) is unnecessary and superfluous because, in common 
language usage, the word ``douche'' has become synonymous with vaginal 
use. The comment added that the agency has codified this class of 
products as ``douche preparations'' in 21 CFR 369.20. The comment 
requested that the statement of identity allow for synonyms for 
``vaginal douche'' such as ``feminine douche,'' ``disposable douche,'' 
and ``douche.'' The comment argued that the term ``vaginal douche'' may 
be too sensitive for certain advertising media and that the requested 
synonyms plus the accompanying labeling would clearly define the 
product as intended for vaginal use only.
     The agency recognizes the sensitivity to use of the word 
``vaginal'' and will take this into consideration in developing 
labeling in the appropriate OTC drug monographs. (See, e.g., the 
labeling developed for hydrocortisone in the tentative final monograph 
for OTC external analgesic drug products (48 FR 5852 at 5868).)
     16. One comment objected to the Vaginal Panel's recommendation in 
proposed Sec. 351.152(b) that the two statements ``Keep this and all 
drugs out of the reach of children'' and ``DOES NOT PREVENT PREGNANCY'' 
appear on the principal display panel of OTC vaginal drug products. The 
comment argued that including such statements on the principal display 
panel is contrary to labeling requirements in other OTC drug 
regulations now in effect in that statements such as these are 
generally required to be displayed in a warnings section next to the 
directions for use. The comment further argued that vaginal douche 
products have not been shown less safe than or different from other OTC 
drug products to the extent that would necessitate inclusion of 
separate warning statements. The comment requested that the Vaginal 
Panel's recommended that proposed Sec. 351.152(b) be deleted and that 
these statements be included with the recommended label warnings in 
proposed Sec. 351.154(a).
     The agency agrees with the comment that special placement of these 
warning statements on the principal display panel is unwarranted. The 
Vaginal Panel recommended that the statement ``Keep this and all drugs 
out of the reach of children'' appear on the principal display panel 
because the attractiveness and colorful appearance of many vaginal drug 
products may encourage children to open and consume the contents (48 FR 
46694 at 46708). The agency is unaware of any evidence that OTC vaginal 
drug products are any more attractive or more likely to be opened and 
consumed by children than other OTC drug products. Therefore, the 
agency has determined that there is no need for special placement of 
this general warning statement in the labeling of OTC vaginal drug 
products. Because existing regulations in Sec. 330.1(g) (21 CFR 
330.1(g)) already require all OTC drugs to contain the warning ``Keep 
this and all drugs out of the reach of children,'' there is no need to 
include this warning in individual OTC drug monographs.
     However, because the Vaginal Panel was concerned that there is a 
commonly held misconception by some people that douching prevents 
pregnancy (48 FR 46694 at 46708), the agency encourages manufacturers 
to voluntarily place the warning ``DOES NOT PREVENT PREGNANCY'' in the 
labeling of vaginal douche products. The agency will discuss vaginal 
drug product labeling regarding prevention of pregnancy and sexually 
transmitted diseases as part of the rulemaking for OTC antifungal drug 
products in a future issue of the Federal Register.
     17. One comment urged deletion of the Vaginal Panel's recommended 
professional labeling statement in proposed Sec. 351.180(b)(3), which 
reads: ``The use of povidone-iodine as a douche may cause a transient 
rise of serum protein-bound iodine.'' The comment argued that in view 
of the Vaginal Panel's conclusion that a transient rise in serum 
protein-bound iodine levels (observed in some individuals) does not 
affect the safety of the drug and has not been shown to have clinical 
significance with respect to thyroid function (48 FR 46694 at 46705), 
the statement is unwarranted. The comment added that inclusion of such 
a statement in professional labeling is misleading because it directs 
unwarranted emphasis to an essentially meaningless event.
     The comment also stated that if the agency decides not to delete 
this statement, the statement should be amended to read as follows: 
``While not affecting its safety, the use of povidone-iodine as a 
douche may cause a transient rise in serum protein-bound iodine in some 
individuals. Such transient elevation returns to normal within 7 to 30 
days and there is no evidence that this has clinical significance with 
respect to thyroid function.'' The comment contended that this revised 
statement would present the full clinical significance of the rise in 
serum protein-bound iodine according to the Vaginal Panel's stated 
findings.
     As discussed in comment 9, the agency intends to consider 
povidone-iodine for vaginal use in the rulemaking for OTC topical 
antimicrobial drug products in a future issue of the Federal Register. 
In the tentative final monographs in which povidone-iodine is a 
Category I ingredient (antifungal (54 FR 51136, December 12, 1989) and 
first aid antiseptic (56 FR 33644, July 22, 1991)), a statement 
regarding the transient rise in protein-bound iodine associated with 
the use of povidone-iodine has not been included in professional 
labeling. Any other professional labeling associated with vaginal use 
of povidone-iodine will be considered as part of the antimicrobial 
rulemaking and will not be further considered here.

 D. Comments on Combinations

     18. One comment requested that the Vaginal Panel's recommended 
list of permitted combinations in proposed Sec. 351.120 be amended to 
provide for combinations of one Category I ingredient from any two, 
three, or four of the various pharmacologic classes. The comment stated 
that there is adequate precedent in the OTC drug review for combining 
Category I ingredients from one pharmacological class with Category I 
ingredients from another pharmacological class, without the necessity 
of elaborate testing of the combination.
     As explained in comment 3, the agency is withdrawing the advance 
notice of proposed rulemaking for OTC vaginal drug products and is 
referring consideration of specific vaginal claims to other appropriate 
OTC drug rulemakings. Likewise, combinations of ingredients for vaginal 
claims will be considered in those respective rulemakings and will not 
be considered here.
     19. The agency recognizes that the Vaginal Panel recommended some 
professional labeling indications for several of the ingredients it 
reviewed. (See Proposed Sec. 351.180, 48 FR 46694 at 46729.) For a 
combination product containing the ingredients dioctyl sodium 
sulfosuccinate (docusate sodium) and sodium lauryl sulfate, the Vaginal 
Panel recommended the indication ``For the treatment of Trichomonas 
vaginalis.'' For a combination product containing the ingredients 
calcium propionate and sodium propionate, the Vaginal Panel recommended 
the indication ``For the treatment of Candida albicans.'' For the 
ingredient povidone-iodine, the Vaginal Panel recommended the 
indication ``Clinically effective in a program of treatment for vaginal 
moniliasis, T-vaginales vaginitis, and nonspecific vaginitis.''
     In the preamble to the Vaginal Panel's report (48 FR 46694 at 
46695), the agency disagreed with the Vaginal Panel's recommendations 
regarding calcium propionate and sodium propionate. Based on previous 
decisions made by the agency with respect to these ingredients under 
the DESI program, the agency placed the professional labeling 
indication recommended by the Vaginal Panel for calcium propionate and 
sodium propionate in Category II. The agency reaffirms that 
categorization in this document.
     The agency also stated in the preamble to the Vaginal Panel's 
report that OTC marketing of these ingredients for the relief of minor 
vaginal irritations could not take place at that time because the 
studies relied upon by the Panel were the same as those reviewed by the 
agency and found to be inadequate under DESI. The agency invited 
comment and data that would support the Panel's recommendations on the 
safety and effectiveness of calcium propionate and sodium propionate as 
ingredients in OTC vaginal drug products. No comments or new data were 
submitted. Therefore, the agency is reaffirming its conclusions that 
these ingredients, singly or in combination, may not be marketed in OTC 
drug products with claims for vaginal use.
     In recommending a professional labeling claim for docusate sodium 
and sodium lauryl sulfate, the Panel relied upon one published study 
(Ref. 1) to support its recommendation. The agency has evaluated this 
study and finds that it is insufficient to determine the safety and 
effectiveness of these ingredients for the treatment of Trichomonas 
vaginalis. The study does not satisfy the criteria for an adequate and 
well-controlled clinical study because it did not include a control 
group. In addition, it was not designed to determine the effect of 
these ingredients in treating Trichomonas but rather to determine the 
effect of pH on the removal of secretions from the vagina. Therefore, 
these ingredients, singly or in combination, may not be marketed in OTC 
drug products with claims (including professional labeling claims) for 
vaginal use.
     Regarding the active ingredient povidone-iodine, the Panel (48 FR 
46694 at 46705) stated that adequate data supported a claim of 
effectiveness against vaginal yeast (candidiasis or moniliasis), T-
vaginales vaginitis and nonspecific vaginitis, but only when used in a 
treatment regimen consisting of the diluted douche and the full 
strength (10 percent) povidone-iodine products. Because the Vaginal 
Panel (48 FR 46694 at 46700) believed that claims of therapeutic 
benefit for treatment of specific vaginal infections must be restricted 
to professional labeling, e.g., for the treatment of trichomoniasis or 
moniliasis, labeling for the full strength (10 percent) product was not 
included in the monograph. However, the agency has since concluded that 
recurring vaginal yeast (Candida) infections can be safely treated OTC. 
The agency is currently reviewing the data the Vaginal Panel considered 
as well as a subsequent petition filed in support of various vaginal 
claims and formulations for povidone-iodine (Ref. 4). The agency will 
discuss the use of povidone-iodine for the treatment of vaginal yeast 
(Candida) infections in a future Federal Register publication as part 
of the rulemaking for OTC antifungal drug products.
    Two clinical studies were cited in the data submission to the OTC 
drug review to support the vaginitis claim (Refs. 2 and 3). The agency 
has reviewed the two clinical studies and has concluded that they are 
insufficient to demonstrate that povidone-iodine is effective in the 
treatment of vaginitis. Neither study satisfies the criteria for 
adequate and well-controlled studies because a control group was not 
included. Therefore, they are insufficient to demonstrate the 
effectiveness of povidone-iodine in the treatment of vaginitis.

 References

     (1) Fischer, R. R., ``Detergent Alkaline Douches,'' Pacific 
Medicine and Surgery, 73:209-212, 1965.
     (2) Shook, D. M., ``A Clinical Study of a Povidone-Iodine 
Regimen for Resistant Vaginitis,'' Current Therapeutic Research, 
5:256-263, 1963.
     (3) Ratzan, J. J., ``Monilial and Trichomonal Vaginitis Topical 
Treatment With Povidone-Iodine Preparations,'' California Medicine, 
110:24-27, 1969.
     (4) Comment No. CP, Docket No. 82N-0291, Dockets Management 
Branch.

 II. The Agency's Conclusions on OTC Vaginal Drug Products

     FDA has considered the comments and other relevant data and 
information available at this time and determined that specific claims 
and ingredients for use in and around the vagina will be included in 
other appropriate OTC drug rulemakings. Accordingly, the advance notice 
of proposed rulemaking published in the Federal Register of October 13, 
1983 (48 FR 46694), which would have added a new subpart B (Vaginal 
Drug Products for Over-the-Counter Human Use) to proposed part 351 
(Vaginal Contraceptive and Other Vaginal Drug Products for Over-the-
Counter Human Use) (proposed 21 CFR part 351), is hereby withdrawn, 
effective February 3, 1994. As discussed above, claims that are 
cosmetic claims only will not be considered in any OTC drug 
rulemakings. Ingredients and drug claims related to use in and around 
the vagina will be considered in other appropriate OTC drug 
rulemakings. The agency has identified the following rulemakings as 
those appropriate for consideration of ingredients and claims for 
vaginal drug uses: (1) Antifungal drug products (docket No. 80N-0476), 
(2) external analgesic drug products (docket No. 78N-0301), (3) skin 
protectant drug products (docket No. 78N-0021), and (4) topical 
antimicrobial drug products (Docket No. 75N-0183).
     The agency emphasizes that it is withdrawing only the advance 
notice of proposed rulemaking for these drug products and that this 
withdrawal does not in any way denigrate the scientific content of the 
report or negate the excellent work of the Vaginal Panel in its long 
efforts to produce it. FDA believes that the information in the Vaginal 
Panel's report will provide valuable guidance to the agency with 
respect to ingredients and vaginal claims for other OTC drug 
rulemakings. Further, this withdrawal of the advance notice of proposed 
rulemaking does not affect the current marketing status of any of the 
products that were considered in the Vaginal Panel's report. This 
withdrawal notice is issued under authority of secs. 201, 501, 502, 
503, 505, 510, 701 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321, 351, 352, 353, 355, 360, 371).
     The agency has determined under 21 CFR 25.24(c)(6) that this 
action is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

    Dated: December 10, 1993.
 Michael R. Taylor,
 Deputy Commissioner for Policy.
[FR Doc. 94-2263 Filed 2-2-94; 8:45 am]
BILLING CODE 4160-01-F