[Federal Register Volume 68, Number 250 (Wednesday, December 31, 2003)]
[Pages 75585-75591]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-32102]



Food and Drug Administration

[Docket No. 2003N-0539]

Over-the-Counter Drug Products; Safety and Efficacy Review

AGENCY: Food and Drug Administration, HHS

ACTION: Request for data and information.


SUMMARY: The Food and Drug Administration (FDA) is announcing a call 
for data for certain categories of ingredients in over-the-counter 
(OTC) drug products that are eligible for the original OTC drug review 
but have not been reviewed by FDA to date. FDA will review the 
submitted data and information as part of its ongoing review of OTC 
drug products to determine whether these ingredients and products are 
generally recognized as safe and effective (GRAS/E) for their labeled 
uses. This document also requests the

[[Page 75586]]

identification of other categories of OTC drug products that were in 
the marketplace when the OTC drug review began on May 11, 1972, or that 
were marketed before December 4, 1975, and describes FDA's general 
regulatory policy governing the marketing of these OTC drug products 
during the pendency of this review.

DATES: Submit data, information, and general comments by June 28, 2004.

ADDRESSES: Submit data and information directly to the Division of OTC 
Drug Products (HFD-560), Center for Drug Evaluation and Research, Food 
and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. Submit 
general comments in writing to the Division of Dockets Management (HFA-
305), 5630 Fishers Lane, rm. 1061, Rockville, MD 20852 or 
electronically to http://www.fda.gov/dockets/ecomments.

Rachanow, Center for Drug Evaluation and Research (HFD-560), Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-


I. Background

    In 1972, FDA established the OTC drug review to evaluate currently 
marketed OTC drug products. The final regulations in part 330 (21 CFR 
part 330) providing for the OTC drug review under 21 CFR 130.301 
(recodified as Sec.  330.10) were published and made effective in the 
Federal Register of May 11, 1972 (37 FR 9464). Since that time, FDA has 
published various calls for data inviting interested parties to submit 
data and information for the advisory review panels to review.\1\ 
During the course of the OTC drug review, advisory review panels 
reviewed many of the categories of OTC drug products included in prior 
call-for-data notices but did not review every category because of 
resource limitations.\2\ Table 1 of this document lists the categories 
of OTC drug products reviewed by all 17 panels and FDA and several 
categories of products that were reviewed by FDA only.

    \1\See 38 FR 31696, November 16, 1973, and 40 FR 38179, August 
27, 1975.
    \2\FDA also identified several categories of marketed OTC drug 
products that were not reviewed by the advisory panels and publish 
subsequent call-for-data notices for those product categories. In 
the Federal Register of December 5, 1989 (54 FR 50240), FDA 
published a request for data and information on ingredients in 
eyewash drug products used for emergency first aid treatment of 
chemical burns of the eyes. FDA publshed a proposed rule for those 
products in the Federal Register of September 19, 1990 (55 FR 
38560), FDA published a request for data and information on 
ingredients contained in products bearing antiplaque and antiplaque-
related claims. The Dental Products Panel completed its review of 
the data and information that were submitted, and FDA published the 
panel's report in the Federal Register of May 29, 2003 (68 FR 

 Table 1.--Categories of OTC Drug Products Reviewed by 17 Panels and/or
  Diaper Rash
  Nails and Scalp
  Alcohols (topical)
  Antiseptics (First aid)
  Antiseptics (Health Care)
  Diaper Rash
Benign Prostatic Hypertrophy
Boil Treatment
Camphorated Oil
Category II/III Ingredients (Phase I)
Category II/III Ingredients (Phase II)
Category II/III Ingredients (Additional)
Corn/Callus Remover
  Nasal Decongestant
Daytime Sedative
Deodorant (Internal)
Digestive Aid
Exocrine Pancreatic Insufficiency
External Analgesic:
  Diaper Rash
  Fever Blister/Cold Sore
  Insect Bites/Stings
  Male Genital Desensitizer
  Poison Ivy/Oak/Sumac
Fever Blister/Cold Sore (Internal)
Hair Grower/Loss
Hormone (topical)
Ingrown Toenail Relief
Insect Repellent (Internal)
Internal Analgesic:
  Leg Muscle Cramps
Nailbiting/Thumbsucking Deterrent
Nighttime Sleep-aid
Oral Health Care:
  Oral Discomfort (Relief)
  Oral Mucosal Injury
  Oral Wound Healing
  Drying Water-Clogged Ears
  Earwax Removal
  Swimmer's Ear
Overindulgence Remedies:
  Prevent Inebriation
Poison Treatment:
  Acute Toxic Ingestion Treatment
Salicylanilides (Tribromsalan)
Skin Bleaching
Skin Protectant:
  Diaper Rash
  Fever Blister/Cold Sore
  Insect Bites/Stings
  Poison Ivy/Oak/Sumac
Smoking Deterrent
Stomach Acidifier
Sweet Spirits of Nitre
Vaginal Contraceptive
Vaginal Drug Products
Wart Remover
Weight Control
Zirconium (Aerosol)

II. The Current Request for Data and Information

    To complete the OTC drug review, FDA is publishing this call-for-
data notice on the following categories of ingredients: (1) Nasal 
moisturizer drug products, (2) urinary analgesic/antiseptic drug 
products, (3) urinary acidifiers and alkalinizers, (4) aloe vera and 
urea, (5) wrinkle remover products, and (6) lubricants and vaginal 
moisturizers. The categories of OTC drugs in this notice include some 
of the categories from the 1973 and 1975 notices that were not reviewed 
and several other categories that the agency has identified that were 
never reviewed. These include urinary analgesics/antiseptics and saline 
nasal products. Interested parties who identify other categories of OTC 
drug products that were in the marketplace when the OTC drug review 
began on May 11, 1972, or that were marketed before December 4, 1975 
(see Sec.  330.13), should submit comments regarding this document to 
the agency about those categories of OTC drug products, including the 
active ingredients in the products and the uses for which the products 
were marketed. Product labels should be provided if available.

[[Page 75587]]

A. Nasal Moisturizer Drug Products

    The agency considers nasal moisturizer products\3\ to be drugs when 
they contain the following or similar ingredients: Sodium chloride, 
normal saline, buffered isotonic saline solution, saline phosphate 
buffer solution, glycerin. A number of these nasal moisturizer products 
have been marketed for several years with various labeling claims. Such 
claims include the following statements:

    \3\In its report on OTC cold, cough, allergy, bronchodilator, 
and antiasthmatic drug products (published in the Federal Register 
of September 9, 1976 (41 FR 38312)), the panel that reviewed these 
products classified saline phosphate buffer solution as an inactive 
ingredient or pharmaceutical necessity, and did not classify it as a 
nasal moisturizer. The panel did not review and evaluate products 
used as nasal moisturizers, and these products were not reviewed and 
evaluated in the various tentative final and final monographs under 
the rulemaking for OTC cold, cough, allergy, bronchodilator, and 
antiasthmatic drug products.

    [sbull]``provides soothing moisture to dry, inflamed nasal 
membranes due to colds, allergies, low humidity, and other minor nasal 
    [sbull]``restores vital moisture to provide prompt relief for dry, 
crusted, and inflamed nasal membranes due to chronic sinusitis, colds, 
low humidity, overuse of nasal decongestant drops and sprays, 
allergies, minor nose bleeds, and other minor nasal irritations''
    [sbull]``use for dry nasal membranes caused by chronic sinusitis, 
allergy, asthma, dry air, oxygen therapy''
    [sbull]``rhinitis medicamentosa, rhinitis sicca, and atrophic 
rhinitis for patients `hooked on nose drops' and glaucoma patients on 
diuretics having dry nasal capillaries''
    [sbull]``a nasal moisturizer formulated to be physiologically 
compatible with nasal membranes, providing soothing relief for clogged 
nasal passages without stinging or burning''
    [sbull]``restores moisture to relieve dry, inflamed nasal membranes 
due to low humidity, colds, allergies, and overuse of nasal 
    FDA currently desires additional data on which to make a 
determination as to the safety, effectiveness, and labeling of these 
products. There may be other labeling statements or formulations of the 
products that are marketed as OTC nasal moisturizers. FDA considers 
many of these claims to be drug claims and believes these products 
should be regulated under the monograph for OTC cough-cold or 
miscellaneous internal drug products. Therefore, FDA requests that 
interested persons who have data and information on the safety and 
effectiveness of nasal moisturizer products submit them to FDA at this 

B. Urinary Analgesic/Antiseptic Drug Products

    FDA is also aware that products marketed as urinary analgesics/
antiseptics and products for too frequent, burning, and painful 
urination have been marketed for a number of years, but have not yet 
been evaluated as part of the OTC drug review.\4\ Other products 
marketed for these uses for a number of years contain methylene blue 
and phenazopyridine hydrochloride (HCl).

    \4\A product containing methenamine, sodium salicylate, 
salicylamide, and benzoic acid was submitted in response to the 1973 
and 1975 call-for-data notices mentioned previously, but has not 
been reviewed to date. This submission is out-of-date and needs to 
be updated before the agency begins its review of these products.

    Phenazopyridine HCl has had a dual prescription/OTC marketing 
status based on the ingredient's extensive marketing history in the 
United States that predates the 1951 Durham-Humphrey Amendments to the 
Federal Food, Drug, and Cosmetic Act (the act). FDA reviewed 
phenazopyridine HCl/sulfonamide combination products under the Drug 
Efficacy Study Implementation (DESI 12056) for the treatment of urinary 
tract infections caused by a sulfonamide-susceptible organism when 
relief of symptoms of pain, burning, or urgency is needed. None of the 
single-entity phenazopyridine HCl drugs marketed at that time or now 
have been the subject of an approved new drug application (NDA).
    In the Federal Register of July 29, 1983 (48 FR 34516), FDA 
published a DESI notice containing conditions for approval and 
marketing of phenazopyridine-containing drug products (single entities 
or fixed combinations). The notice announced certain required labeling 
statements for phenazopyridine-containing drug products indicated for 
use in relieving symptoms associated with a urinary tract infection, 
and certain required labeling for all phenazopyridine-containing drug 
products. FDA recommended the following labeling requirements for 
phenazopyridine-containing drug products (single entities or fixed 
combinations) for use in the treatment of urinary tract infections:
    1. The following information shall be disclosed in the INDICATION 
section (adapted to the labeling of particular drug products): 
Treatment of a urinary tract infection with phenazopyridine HCl or a 
combination drug product containing phenazopyridine HCl should not 
exceed 2 days because there is lack of evidence that the combined 
administration of phenazopyridine HCl and an antibacterial provides 
greater benefit than administration of the antibacterial alone after 2 
    2. The part of the INDICATION section pertaining to the use of the 
product in urinary tract infections shall also refer to the DOSAGE and 
    3. In its dosage and dosing interval recommendations pertaining to 
the use of the product in urinary tract infections, the DOSAGE and 
ADMINISTRATION section shall show that the product is only indicated 
for up to 2 days (the effect of phenazopyridine HCl should not be 
relied upon after 48 hours).
    The DESI notice also contained the following labeling requirement 
for all drug products containing phenazopyridine:
    The following statement shall be included in the CARCENOGENESIS 
subsection of the PRECAUTION section of the labeling:
    Long-term administration of phenazopyridine hydrochloride has 
induced neoplasia in rats (large intestine) and mice (liver). 
Although no association between phenazopyridine hydrochloride and 
human neoplasia has been reported, adequate epidemiological studies 
along these lines have not been conducted.
    This information came from a National Cancer Institute technical 
report (Ref. 1). FDA is not aware of any epidemiological studies that 
have been done since the report was published in 1978.
    The 1983 DESI notice states that the product considered (Azo 
Gantanol) contained 500 milligrams (mg) of sulfamethoxazole 
(antibacterial component) and 100 mg of phenazopyridine HCl (analgesic 
component) per tablet, and this combination is effective only for the 
first 48-hour treatment period (four tablets initially followed by two 
tablets every 12 hours, with the last dose administered at 36 hours). 
There is no evidence that the phenazopyridine HCl component has a 
beneficial effect on symptoms beyond 48 hours. Therefore, after initial 
treatment with the combination product, further treatment should be 
continued only with the sulfonamide.
    The way the labeling information appeared in the notice indicated 
that 200 mg of phenazopyridine was the prescription dose. Products 
containing lesser amounts (e.g., 190 or 195 mg) have been marketed OTC. 
The recommended dosage is three times a day after meals. OTC drug 
products containing phenazopyridine HCl as a urinary analgesic are 
usually labeled: ``Can be used up to 3 times daily for 2 days 
maximum.'' One product surveyed (Ref. 2) does not contain the required

[[Page 75588]]

carcinogenesis statement on the outer package labeling but does have 
the statement in a package insert included inside the package.
    FDA issued a Compliance Policy Guide on October 1, 1980 (Ref. 3), 
revised on May 22, 1987 (Ref. 3), that addressed urinary tract 
preparations containing phenazopyridine HCl. FDA advised that it was 
not taking regulatory action against products containing this 
ingredient and lackingand lacking a prescription legend or full-
disclosure labeling [based on their deferral to the OTC drug review].
    FDA has a number of questions and issues that it plans to consider 
when it evaluates phenazopyridine HCl for urinary tract analgesic/
antiseptic use as part of this review.
    1. Is this condition appropriate for self medication?
    2. If the answer to the first question is yes, should the product 
labeling mention the possible need for treatment with an antibacterial 
drug also?
    3. Is there a valid basis for having single-ingredient prescription 
products with a 200 mg dosage and OTC products with a 190 to 195 mg 
dosage? What data support these dosages?
    4. Have any epidemiological studies been done since 1978 that 
address the neoplasia findings in the National Cancer Institute 
technical report (Ref. 1)?
    5. Are the neoplasia findings of sufficient concern to restrict 
this drug to prescription status?
    6. Do consumers adequately understand the required carcinogenesis 
labeling statement? If the answer is no, how should this statement be 
    7. Should the carcinogenesis labeling statement be required to 
appear on the outer package labeling, or is it adequate that it appear 
only in a package insert?
    8. Provide updated safety data both from the literature and from 
adverse event reports for the last 20 years, especially those adverse 
events reported to companies that market these products.
    FDA invites parties interested in the OTC status of this ingredient 
to submit their answers to these questions and any supporting data to 
the Division of Dockets Management as comments to this notice so that 
this information will be publicly available when FDA reviews this 
ingredient. Adverse event reports should not include names or telephone 

C. Urinary Acidifiers and Alkalinizers

    FDA is also aware of OTC drug products that have been marketed as 
urinary acidifiers and urinary alkalinizers. Ammonium chloride and 
ascorbic acid have been used as OTC urinary acidifiers, and sodium 
bicarbonate has been used as an OTC urinary alkalinizer. These products 
have not been included in any previous call-for-data notices as part of 
the OTC drug review. Therefore, at this time FDA invites interested 
persons to submit data or information on these and any other 
ingredients for use as OTC urinary acidifiers and alkalinizers.

D. Aloe Vera and Urea

    Aloe vera has been present in a variety of OTC drug products. It 
has been listed as both an active and inactive ingredient. It has been 
marketed as a skin remedy for minor cuts, burns, abrasions, and for 
relief of minor irritations of the vagina. The Advisory Review Panel on 
OTC Contraceptives and Other Vaginal Drug Products (Vaginal Drug 
Products Panel) placed stabilized aloe vera in Category III (for 
effectiveness) for the relief of minor irritations of the vagina 
(advance notice of proposed rulemaking (ANPRM), 48 FR 46694 at 46711 to 
46712, October 13, 1983). The panel mentioned that treatment of minor 
burns, insect bites, and other conditions in which a wet dressing of 
aloe vera is used has been widely reported and handed down from 
generation to generation. FDA withdrew this ANPRM in the Federal 
Register of February 3, 1994 (59 FR 5226), because 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, FDA planned to 
consider the ingredients and indications from the vaginal drug products 
ANPRM in those other rulemakings, as appropriate. However, no 
submissions for aloe vera were made to the other rulemakings. Because 
there may not have been an adequate opportunity for interested parties 
to submit data and information on aloe vera to those rulemakings, FDA 
invites interested parties to submit any available data and information 
at this time before it finalizes the monographs for OTC topical 
antimicrobial and external analgesic drug products. The monograph for 
OTC topical antifungal drug products is finalized (21 CFR part 333, 
subpart C), so any interested parties should submit any data and 
information on aloe vera for this use as a petition to amend the final 
    Urea has been marketed as an antipruritic and keratolytic in a 
number of topical products, with claims that range from ``drug'' 
(relieves itching) to ``cosmetic'' (for total body dry skin care,soften 
dry rough skin). Several submissions on products containing urea were 
made to the Advisory Review Panel on OTC Miscellaneous External Drug 
Products, but that panel did not complete its review of those 
submissions before it was disbanded. The submissions need to be updated 
for FDA to consider them at this time. No data or information on urea 
have been submitted to the rulemaking for OTC external analgesic drug 
products. At this time, FDA invites any interested parties to submit 
data or information on the use of urea as an external analgesic drug 
product or for any other OTC drug use.

E. Wrinkle Remover Products

    Whether a wrinkle remover product should be regulated as a drug or 
a cosmetic depends on the claims the manufacturer makes for the 
product. The regulation of cosmetics is covered in 21 CFR part 700. 
Manufacturers of these products should examine their labeling for these 
products and to determine if the products products should be submitted 
to the OTC drug review for evaluation. Manufacturers should determine 
if the ingredients in those products affect the structure of the skin 
in some physiological way and, thus, should be submitted for review as 
drug ingredients section (see section 201(g)(1)(C) of the act (21 
U.S.C. 321(g)(1)(C)). For example, some products marketed since 1971 
contain alpha hydroxy acids and beta hydroxy acids. These ingredients 
are included in this request for data and information.

F. Lubricants and Vaginal Moisturizers

    The Vaginal Drug Products Panel reviewed OTC drug products for a 
number of vaginal uses (48 FR 46694). However, those uses did not 
include vaginal lubricant or moisturizer. A number of products are 
marketed as a lubricant, personal lubricant, or lubricating jelly. 
These products have uses that include: ``For personal lubrication when 
vaginal dryness causes discomfort,'' ``acts as a moisturizer for 
vaginal dryness,'' ``enhances the comfort and ease of intimate 
activity,'' and ``enhances sexual pleasure by adding to the body's 
natural lubrication.'' Other products are marketed as lubricating 
spermicides [lubricant plus nonoxynol-9] or as a lubricant with 
nonoxynol-9. These products have claims that state ``spermicide, 
nonoxynol-9, plus safe water-soluble personal lubrication, feels 
natural and helps enhance sexual pleasure, lubricating protection 
against unplanned pregnancy,'' and ``enhances sexual pleasure by adding 
to the body's natural lubrication, not a contraceptive;

[[Page 75589]]

however, because it may kill some sperm, it should not be used if 
pregnancy is desired.'' FDA considers claims related to relief of 
discomfort and claims related to the comfort and ease of sexual 
activity to be drug claims as they relate to the mitigation or 
treatment of disease (section 201(g)(1)(B) of the act) or use of a 
product to affect the structure or function of the body (section 
201(g)(1)(C) of the act).
    Some of these lubricant products also have claims such as: ``For 
[or eases] insertion of rectal thermometers, enemas, douches, and 
similar types of nozzles, [and tampons and condoms]'' and ``widely used 
in gynecological and hospital procedures.'' Such claims make these 
products medical devices, and FDA has regulated them as such since 
1976. FDA regulations in 21 CFR part 880 subpart G list products that 
are general hospital and personal use miscellaneous devices. The 
regulation in 21 CFR 880.6375 entitled ``patient lubricant'' states: 
``A patient lubricant is a device intended for medical purposes that is 
used to lubricate a body orifice to facilitate entry of a diagnostic or 
therapeutic device.'' Claims related to insertion of or facilitating 
use of rectal thermometers, enemas, douches, tampons, and condoms are 
considered device claims and are not included as part of this call for 
data. As these products with device claims can also have drug claims as 
discussed previously, FDA invites the submission of data to support the 
drug claims as part of this call for data.
    Products marketed as a vaginal moisturizer have claims such as 
``replenishes your natural moisture for days at a time,'' ``with 
regular use, provides continuous vaginal moisture for most women,'' and 
``safe immediate relief of vaginal dryness.'' FDA also considers these 
to be drug claims because they discuss affecting the structure or 
function of the body and, in some cases, may relate to the mitigation 
of a disease. Thus, they are also part of this call for data. FDA does 
not consider these uses of lubricants or vaginal moisturizers to be 
cosmetic claims because they do not relate to ``cleansing, beautifying, 
promoting attractiveness, or altering the appearance'' (see section 
201(i) of the act).

G. Categories of Unreviewed Drug Products and Ingredients

    The categories of unreviewed drug products listed in the following 
paragraphs are included in this call for data. The ingredients listed 
under each category heading are those that FDA has identified as 
possibly being in these products. This list is not intended to be all-
inclusive. Manufacturers of drug products in categories not previously 
reviewed or that contain ingredients not listed herein should submit 
appropriate information to FDA.

Ammonia as a reflex stimulant
  Ammonia inhalants, aromatic spirits of ammonia
Bed-wetting deterrents
Blemish remedies (excluding topical acne active ingredients in 21 CFR
 310.545(a)(1) and 333.310)
  Allantoin, aloe vera gel, calamine, ethyl alcohol, eugenol, menthol,
   oil of eucalyptus, oil of peppermint, propylene glycol, sodium
   alkylarylpolyether sulfonate, titanium dioxide, triclocarban,
Breast creams (for use when nursing)
  Cetyl alcohol, cocoa butter, cod liver oil, dimethicone, glycerin,
   glyceryl monostearate, hard fat, lanolin, mineral oil, petrolatum,
   white petrolatum
Bunion remedies
Drawing salves (excluding products labeled for the treatment of boils in
 21 CFR 310.531) --includes products labeled for the drawing or removal
 of splinters, slivers, or similar items
  Ergot fluid extract, ichthammol, juniper tar (oil of cade), magnesium
   sulfate, pine tar, rosin, rosin cerate, sulfur
Foot balms, baths, and creams (excluding topical antifungal active
 ingredients in 21 CFR 310.545(a)(22) and 333.210) --including claims
 for relieving foot muscle strains and soreness from working out
  Amyl salicylate, benzalkonium chloride, benzocaine, cajeput oil,
   carbolic acid, di-isobutyl phenoxy ethoxy ethyldimethyl benzyl
   ammonium chloride, essential oils, formalin, glyceryl monostearate, 8-
   hydroxyquinoline, iodized botanical oil, iron sulfate, isopropyl
   alcohol, lanolin, lithium chloride, magnesium sulfate, methyl
   salicylate, natural pine needle oil, o-benzyl-p-chlorophenol, oil of
   eucalyptus, oil of peppermint, oil of thyme, potassium iodide,
   propylene glycol, sodium bicarbonate, sodium chloride, sodium
   hypochloride, sodium lauryl sulfate, sodium sesquicarbonate, sodium
   sulfate, talc, tragacanth mucilage, trisodium phosphate, water
   soluble chlorophyllins, witch hazel, zinc oxide
Impotency cures
  Yohimbine, yohimbine hydrochloride
Impregnated body wraps for weight reduction
  Amino acids, collagen, magnesium sulfate
Lubricants and vaginal moisturizers
  Benzoic acid, carbomer 934P, carbopol 940, chlorhexidine gluconate,
   glucono delta lactone, glycerin, hydrogenated palm oil glyceride,
   hydroxyethylcellulose, mineral oil, natrosol 250H, nonoxynol-9,
   polycarbophil, polysorbate 60, polyethylene glycol 300,
   polyquaternium, propylene glycol, sodium hydroxide, sorbic acid,
Medicated bath preparations
  Acetylated lanolin, alkyl aryl polyether alcohol, benzophenone-3,
   colloidal sulfur, cottonseed oil, di-isopropyl sebacate,
   drometrizole, iron sulfate, isopropyl myristate, isopropyl palmitate,
   isostearic acid, lanolin alcohols extract, lanolin oil, liquid
   petrolatum, lithium chloride, magnesium sulfate, mineral oil, natural
   and essential oils, nonoxynol-5, octoxynol-3, PEG-4 dilaurate, PEG-8
   dioleate, PEG-40 sorbitan peroleate, PEG-200 dilaurate, Peru balsam,
   PPG-15, pine needle oil, potassium iodide, stearyl ether oleth-2,
   sodium bicarbonate, sodium carbonate, sodium chloride, sodium
   hyposulfate, sodium lauryl sulfate, sodium sesquicarbonate, sodium
   sulfate, tar distillate, vitamin E, water soluble chlorophyllins
Nasal moisturizers
  Glycerin, buffered isotonic saline solution, buffer solution, isotonic
   saline solution, normal saline, sodium chloride, saline phosphate
Nonantimicrobial skin wound cleansers (previously listed as
  Tincture of Green Soap, phenol sodium, poloxamer 188
Prickly heat products
  Aluminum hydroxide gel, zinc carbonate, zinc oxide
Skin protectant blister guard
  Beta-hydroxyquinolone, eugenol, pyroxylin solution
Urethral creams for males
Urinary acidifiers
  Ammonium chloride, ascorbic acid
Urinary alkalinizers
  Sodium bicarbonate
Urinary analgesics/antiseptics
  Benzoic acid, methenamine, methylene blue, phenazopyridine,
   phenazopyridine HCl, salicylamide, sodium salicylate
Wet dressings (excluding astringent active ingredients in 21 CFR
 310.545(a)(18)(ii) and 347.10)
  Aloe vera, calcium polysulfide, calcium thiosulfate, oxyquinoline
   sulfate, sodium propionate
Wound wash saline
  Sodium chloride solution, sterile sodium chloride solution
Wrinkle removers
  Alpha hydroxy acids

[[Page 75590]]

  Alpha-hydroxycaprylic acid, alpha-hydroxyoctanoic acid, alpha-
   hydroxyethanoic acid and ammonium alpha-hydroxyetnanoate, alpha
   hydoxy and botanical complex, glycolic acid, glycolic acid and
   ammonium glycolate, glycomer in crosslinked fatty acids alpha
   nutrium, hydroxycaprylic acid, L-alpha hydroxy acid, lactic acid,
   mixed fruit acid, sugar cane extract, tri-alpha hydroxy fruit acids,
   triple fruit acid
  Beta hydroxy acids
  Beta hydroxybutanoic acid, salicylic acid\1\, trethocanic acid, tropic
  Alpha and beta hydroxy acids
  Citric acid, malic acid
  Other ingredients
Egg albumin, magnesium aluminum silicate, protein, sodium silicate
\1\ From a chemist's perspective, based on its chemical structure,
  salicylic acid is not a true beta hydroxy acid. However, cosmetic
  companies often refer to this ingredient as a beta hydroxy acid.
  Consequently, many consumers think of it as one as well.

III. Categories That Will Not Be Reviewed

A. Categories Reclassified or Considered as Foods

    The categories ``salt substitutes,'' ``salt tablets,'' and 
``sweeteners'' were included in the 1975 call-for-data notice (40 FR 
38179 at 38183). These types of products are currently regulated as 
foods and will not be further considered as part of the OTC drug 
review. During the course of the review, several parties inquired 
whether ``oral electrolyte replacement'' products and ``weight 
increasing'' products would be included in the review because these 
product categories were not mentioned in the 1973 and 1975 call-for-
data notices. Oral electrolyte replacement products intended to treat 
diarrhea are regulated as medical foods under section 529(b)(3) of the 
act (21 U.S.C. 360ee(b)(3) and 21 CFR 101.9(j)(8)), and products for 
``weight gain'' are considered foods (21 U.S.C. 301 et seq.).

B. Categories Reclassified or Considered as Medical Devices

    In several instances, since 1975, FDA determined that certain types 
of products previously regulated as drugs should be regulated as 
medical devices and changed its regulatory approach accordingly (Ref. 
4). These products include a spray-on dressing that does not contain a 
drug component and a ``device incorporating a drug component with the 
combination product having the primary intended purpose of fulfilling a 
device function.'' This latter group of products includes a skin 
closure or bandage with an antimicrobial agent and a wound dressing 
with an antimicrobial agent. These products are considered combination 
products regulated by the Center for Devices and Radiological Health 
(CDRH), using device authorities under the act.
    A liquid bandage\5\ is defined in 21 CFR 880.5090 as ``a sterile 
device that is a liquid, semiliquid, or powder and liquid combination 
used to cover an opening in the skin or as a dressing for burns. The 
device is also used as a topical skin protectant.'' A medical adhesive 
tape and adhesive bandage is defined in 21 CFR 880.5240 as:

    \5\The categories ``liquid bandages (sprays)--protective skin 
preparations'' and ``medicated bandages'' were in the 1975 call-for-
data notice (40 FR 38179 at 38181), which listed 23 active 
ingredients possibly used in these products. These ingredients in 
products for these specific uses would not be considered OTC drug 
active ingredients.

    ``* * * a device intended for medical purposes that consists of 
a strip of fabric material or plastic, coated on one side with an 
adhesive, and may include a pad of surgical dressing without a 
disinfectant. The device is used to cover and protect wounds, to 
hold together the skin edges of a wound, to support an injured part 
of the body, or to secure objects to the skin.''
FDA is not including any of these device products in this current call 
for data.

IV. Request for Data and Information

    FDA invites the submission of data, published and unpublished, and 
other information, pertinent to all active ingredients in these and 
other eligible unreviewed OTC drug categories (see section II of this 
document). Interested persons should include any consumer comprehension 
data relating to the OTC use of drug products containing these 
ingredients. These data and information will contribute to the 
following objectives:
    [sbull] Facilitate FDA's review and aid in its determination of 
whether these OTC drugs for human use are generally recognized as safe 
and effective and not misbranded under their recommended conditions of 
use, and
    [sbull] Provide all interested persons an opportunity to present 
for consideration the best data and information available to support 
the stated claims for these products. Any relevant data and information 
on these drug products that may have been submitted to earlier 
rulemakings or in response to earlier call-for-data notices should be 
updated and resubmitted to facilitate FDA's review of these products.
    FDA also requests manufacturers to identify other OTC drug products 
that still need to be reviewed to determine if they are GRAS/E for OTC 
use. For OTC drug products that should have been submitted for review 
but for which data and information have not been received, FDA may not 
consider those products to be GRAS/E for OTC use. In accordance with 
section 201(p) of the act, such drug products would be considered new 
drugs and would need an NDA to be marketed.
    In the Federal Register of January 23, 2002 (67 FR 3060), FDA 
published a final rule providing additional criteria and procedures for 
classifying OTC drugs as GRAS/E and not misbranded. The procedures 
identified in that rule apply to OTC drugs initially marketed in the 
United States after the OTC drug review began in 1972 and to OTC drugs 
without any U.S. marketing experience. This notice is not intended to 
apply to ingredients covered by the additional criteria and procedures 
identified in that rule.
    This notice also does not apply to new chemical entities that have 
not previously been marketed for OTC use, regardless of the claims. 
These products should be submitted to FDA for evaluation in an NDA 
under 21 CFR part 314.
    Manufacturers submitting data and information in response to this 
call for data should include any information (e.g., information showing 
when the product was first marketed in the United States) relating to 
the regulatory status of their product under the general regulatory 
policy described in the next section of this document. If such 
information does not exist or is found to be inadequate, such products 
may be at risk of regulatory action by FDA.

V. General Regulatory Policy

    In order for a product to be eligible for the OTC drug review that 
began on May 11, 1972, the product or similarly formulated and labeled 
products had to be marketed as OTC drugs at the inception of the OTC 
drug review, which date was later extended to on or before December 4, 
1975. Prescription drug products were also eligible for the review, as 
long as they continued to be marketed on a prescription basis while FDA 
evaluated data to ascertain whether the ingredient or combination of 
ingredients in the product could be proposed as GRAS/E for OTC use.
    FDA may exercise its enforcement discretion to permit OTC drug 
products that do not have an approved NDA during the pendency of the 
OTC drug review to be marketed provided the following conditions are 
    1. The product or similarly formulated and labeled products were 
marketed as OTC drugs at the inception

[[Page 75591]]

of the OTC drug review on May 11, 1972, a date that was later extended 
to on or before December 4, 1975 (see Sec.  330.13).
    2. Such product does not constitute a hazard to health.
    3. The product formulation is not regarded regarded to be a 
prescription drug within the meaning of section 503(b) of the act (21 
U.S.C. 353(b)).
    4. The product is an OTC drug and does not bear claims for serious 
disease conditions that require the attention and supervision of a 
licensed practitioner.
    To be considered in this review, eight copies of the data and 
information must be submitted, preferably bound, indexed, and on 
standard size paper (approximately 8[bdfrac12] by 11 inches). FDA 
suggests that all submissions be in the format described in Sec.  
    In accordance with Sec.  330.10(a)(2), FDA will handle all 
submitted data and information as confidential except the general 
comments submitted to the docket in response to this notice and the 
answers to the questions and specific information requested on 
phenazopyridine HCl in section II.B of this document. FDA wants the 
answers to the questions and the specific information on 
phenazopyridine HCl to be publicly available when it reviews this 
ingredient so that all interested parties will have access to this 
information and be able to participate fully in the deliberations. 
However, FDA will put all submitted data and information on public 
display in the Division of Dockets Management (see ADDRESSES) 30 days 
after publication of any proposed rules resulting from the review of 
the submitted material, except to the extent that the person submitting 
it demonstrates that it falls within the confidentiality provisions of 
18 U.S.C. 1905, 5 U.S.C. 552(b), or section 301(j) of the act (21 
U.S.C. 331(j)). At the time of publication, FDA will provide an address 
where requests for confidentiality should be submitted.
    Data and information should be addressed to the Division of OTC 
Drug Products (see ADDRESSES). Data submitted after the closing of the 
comment period (see DATES section) will not be considered except by 
petition under 21 CFR 10.30. Interested persons may submit written or 
electronic comments to the Division of Dockets Management before the 
closing date. Three paper copies of all mailed comments are to be 
submitted. Individuals submitting written comments or anyone submitting 
electronic comments may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document and may be accompanied by a supporting memorandum or brief. 
Received comments may be seen in the Division of Dockets Management 
between 9 a.m. and 4 p.m., Monday through Friday.

VI. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. ``Bioassay of Phenazopyridine Hydrochloride for Possible 
Carcinogenicity,'' National Cancer Institute Carcinogenesis 
Technical Report Series No. 99, U.S. Department of Health, 
Education, and Welfare, Publication No. NIH 78-1349, 1978.
    2. Labeling for Uristat (Urinary Pain Relief Tablets).
    3. Food and Drug Administration, Compliance Policy Guides, No. 
7132b.04, issued October 1, 1980, revised May 22, 1987.
    4. Food and Drug Administration, Intercenter Agreement Between 
the Center for Drug Evaluation and Research and the Center for 
Devices and Radiological Health, October 31, 1991.

    Dated: December 22, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-32102 Filed 12-30-03; 8:45 am]