Topical Antimicrobial Drug Products for Over-the-Counter Human Use; Tentative Final Monograph for Health-Care Antiseptic Drug Products

SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of

proposed rulemaking in the form of an amended tentative final monograph

that would establish conditions under which over-the-counter (OTC)

topical health-care antiseptic drug products are generally recognized

as safe and effective and not misbranded. FDA is issuing this notice of

proposed rulemaking to amend the previous notice of proposed rulemaking

on topical antimicrobial drug products (see the Federal Register of

January 6, 1978, 43 FR 1210) after considering the public comments on

that notice and other information in the administrative record for this

rulemaking. FDA is also requesting data and information concerning the

safety and effectiveness of topical antimicrobials for use as hand

sanitizers or dips. This proposal is part of the ongoing review of OTC

drug products conducted by FDA.

DATES: Written comments, objections, or requests for an oral hearing on

the proposed regulation before the Commissioner of Food and Drugs by

December 14, 1994. Because of the length and complexity of this

proposed regulation, the agency is allowing a period of 180 days for

comments and objections instead of the normal 60 days. New data by June

19, 1995. Comments on the new data by August 17, 1995. Written comments

on the agency's economic impact determination by December 14, 1994.

ADDRESSES: Written comments, objections, new data, or requests for an

oral hearing to the Dockets Management Branch (HFA-305), Food and Drug

Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug

Evaluation and Research (HFD-810), Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: In the Federal Register of September 13,

1974 (39 FR 33103), 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 topical antimicrobial drug products, together with

the recommendations of the Advisory Review Panel on OTC Topical

Antimicrobial I Drug Products (Antimicrobial I 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 November 12, 1974. Reply comments in response to

comments filed in the initial comment period could be submitted by

December 12, 1974. In response to numerous requests, the agency issued

a notice in the Federal Register of October 17, 1974 (39 FR 37066)

granting an extension of the deadline for comments until December 12,

1974, and for reply comments until January 13, 1975.

In the Federal Register of January 6, 1978 (43 FR 1210), FDA

published, under Sec. 330.10(a)(7), a notice of proposed rulemaking to

establish a monograph for OTC topical antimicrobial drug products,

based on the recommendations of the Antimicrobial I Panel and the

agency's response to comments submitted following publication of the

advance notice of proposed rulemaking. Interested persons were invited

to submit objections or requests for oral hearing by February 6, 1978.

In response to numerous requests to extend the time period for

submitting objections or requests for oral hearing, the agency issued a

notice in the Federal Register of February 3, 1978 (43 FR 4637)

granting an extension of the deadline to March 6, 1978. During this

time period, the agency received 6 petitions that requested reopening

the administrative record and 11 requests for an oral hearing. In a

notice published in the Federal Register of March 9, 1979 (44 FR

13041), the agency deferred action on the requests for a hearing, but

granted the petitions to reopen the record to allow interested persons

to submit comments and any new or additional data by June 7, 1979, and

reply comments by July 9, 1979. FDA also stated its intent to publish

an updated (amended) tentative final monograph based on the review and

evaluation of new submissions and a reevaluation of existing data.

In a notice published in the Federal Register of October 26, 1979

(44 FR 61609), the agency again reopened the administrative record for

the submission of new data by March 26, 1980, and for comments on the

new data by May 27, 1980. This action was taken to permit manufacturers

to submit the results of testing to FDA as expeditiously as possible

prior to establishment of a final monograph.

Subsequent to the June 7, 1979, closing date for the submission of

new data, and prior to the October 26, 1979, reopening of the

administrative record, data and information were submitted to FDA. In a

notice published in the Federal Register of March 21, 1980 (45 FR

18398), the agency advised that it had reopened the administrative

record for OTC topical antimicrobial drug products to allow for

consideration of data and information that had been filed in the

Dockets Management Branch after the date the administrative record on

the tentative final monograph had officially closed on March 6, 1978.

The agency concluded that any new data and information filed prior to

March 21, 1980, should be available to the agency in developing a

proposed regulation in the form of a tentative final monograph.

In a notice published in the Federal Register on January 5, 1982

(47 FR 436), the agency advised that it had again reopened the

administrative record for OTC topical antimicrobial drug products to

allow for consideration of the recommendations of the Advisory Review

Panel on OTC Miscellaneous External Drug Products (Miscellaneous

External Panel) on mercury-containing drug products. Interested persons

were invited to submit comments by April 5, 1982, and reply comments by

May 5, 1982. FDA stated that the proceeding to develop a monograph for

mercury-containing drug products would be merged with the general

proceeding to establish a monograph for OTC topical antimicrobial drug

products.

In a notice published in the Federal Register on May 21, 1982 (47

FR 22324), the agency advised that it had again reopened the

administrative record for OTC topical antimicrobial drug products to

allow for consideration of the recommendations of the Miscellaneous

External Panel on alcohol drug products. Interested persons were

invited to submit comments by August 19, 1982, and reply comments by

September 20, 1982. The notice stated that the proceeding to develop a

monograph for alcohol drug products would be merged with the general

proceeding to establish a monograph for OTC topical antimicrobial drug

products.

In the Federal Register of September 7, 1982 (47 FR 39406), FDA

issued a notice to reopen the administrative record for OTC topical

antimicrobial drug products to allow for consideration of the

Miscellaneous External Panel's recommendations on topical antimicrobial

drug products used for the treatment of diaper rash. The agency

discussed topical antimicrobial active ingredients for this use in the

Federal Register of June 20, 1990 (55 FR 25246).

In accordance with Sec. 330.10(a)(10), the data and information

considered by the Panels were put on public display in the Dockets

Management Branch (address above), after deletion of a small amount of

trade secret information. In response to the previous tentative final

monograph and the advance notice of proposed rulemaking for mercury-

containing drug products and the advance notice of proposed rulemaking

for alcohol drug products, 4 drug manufacturers' associations, 44 drug

manufacturers, 1 medical device manufacturer, 1 drug distributor, 2

medical schools, 2 research laboratories, 1 law firm, and 1 consulting

firm submitted comments. Copies of the comments received are also on

public display in the Dockets Management Branch.

The advance notice of proposed rulemaking, which was published in

the Federal Register of September 13, 1974 (39 FR 33103), was

designated as a ``proposed monograph'' in order to conform to

terminology used in the OTC drug review regulations (Sec. 330.10).

Similarly, the notice of proposed rulemaking, which was published in

the Federal Register of January 6, 1978 (43 FR 1210), was designated as

a ``tentative final monograph.'' The present document is also

designated as a ``tentative final monograph.'' The legal status of each

tentative final monograph, however, is that of a proposed rule. The

present document is a reproposal regarding health-care antiseptic drug

products.

This antimicrobial rulemaking is broad in scope, encompassing

products that may contain the same active ingredients, but are labeled

and marketed for different intended uses. For example, one group of

products is primarily used by consumers for ``first aid'' and includes

skin antiseptics, skin wound cleansers, and skin wound protectants.

Another group of products, antiseptic handwashes, are used by consumers

on a more frequent, even daily, basis and includes products for

personal use in the home, such as when caring for invalids and during

family illness. A third group of products is generally intended for use

by health professionals and includes health-care personnel handwashes,

patient preoperative skin preparations, and surgical hand scrubs.

In order to expedite the completion of the first aid section of the

antimicrobial monograph, the agency published a separate tentative

final monograph for these products in the Federal Register of July 22,

1991 (56 FR 33644). The non-first aid uses of topical antimicrobials,

now identified as ``health-care antiseptics,'' are addressed in this

document. Although the amended tentative final monographs for first-aid

antiseptics and health-care antiseptics are being published separately,

both categories will eventually be included under part 333 (21 CFR part

333).

The agency also has decided that OTC topical antimicrobial and

topical antibiotic drug products should be included within the same

monograph. Although an advance notice of proposed rulemaking to

establish a monograph for OTC topical antibiotic drug products was

published under part 342 (21 CFR part 342) on April 1, 1977 (42 FR

17642), the final monograph for those products was issued on December

11, 1987 (52 FR 47312) as a new subpart of the OTC topical

antimicrobial monograph, part 333, subpart B--Topical First Aid

Antibiotic Drug Products. Subpart A will cover first aid antiseptic

drug products; subpart C will cover antifungal drug products; subpart D

covers acne drug products; and new subpart E will cover health-care

antiseptic drug products.

In this tentative final monograph (proposed rule) to establish

subpart E of part 333, FDA states its position on the establishment of

a monograph for OTC health-care antiseptic drug products. This document

addresses only those comments and data concerning the previous

antimicrobial tentative final monograph that are related to ``non-first

aid uses,'' including products for personal use in the home and

products used by health-care professionals.

This proposal constitutes FDA's reevaluation of the January 6, 1978

tentative final monograph based on the comments received and the

agency's independent evaluation of the Miscellaneous External Panel's

reports on OTC alcohol and mercury-containing drug products and the

comments received. The following sections of the January 6, 1978

tentative final monograph for topical antimicrobial drug products are

being addressed in this document: Secs. 333.1, 333.3, 333.30, 333.50,

333.85, 333.87, 333.97, and 333.99. The following sections of the

advance notice of proposed rulemaking for alcohol drug products are

being addressed in this document: Secs. 333.55 and 333.98.

Modifications have been made for clarity and regulatory accuracy and to

reflect new information. Such new information has been placed on file

in the Dockets Management Branch (address above). These modifications

are reflected in the following summary of the comments and FDA's

responses to them. (See section I.)

The OTC drug procedural regulations (21 CFR 330.10) provide that

any testing necessary to resolve the safety or effectiveness issues

that formerly resulted in a Category III classification, and submission

to FDA of the results of that testing or any other data, must be done

during the OTC drug rulemaking process before the establishment of a

final monograph. Accordingly, FDA does not use the terms ``Category I''

(generally recognized as safe and effective and not misbranded),

``Category II'' (not generally recognized as safe and effective or

misbranded), and ``Category III'' (available data are insufficient to

classify as safe and effective, and further testing is required) at the

final monograph stage. In place of Category I, the term ``monograph

conditions'' is used; in place of Categories II and III, the term

``nonmonograph conditions'' is used. This document retains the concepts

of Categories I, II, and III at the tentative final monograph stage.

The agency advises that the conditions under which the drug

products that are subject to this monograph would be generally

recognized as safe and effective and not misbranded (monograph

conditions) will be effective 12 months after the date of publication

of the final monograph in the Federal Register. On or after that date,

no OTC drug product that is subject to the monograph and that contains

a nonmonograph condition, i.e., a condition that would cause the drug

to be not generally recognized as safe and effective or to be

misbranded, may be initially introduced or initially delivered for

introduction into interstate commerce unless it is the subject of an

approved application or abbreviated application (hereinafter called

application). Further, any OTC drug product subject to this monograph

that is repackaged or relabeled after the effective date of the

monograph must be in compliance with the monograph regardless of the

date the product was initially introduced or initially delivered for

introduction into interstate commerce. Manufacturers are encouraged to

comply voluntarily with the monograph at the earliest possible date.

In the advance notice of proposed rulemaking for OTC topical

antimicrobial drug products (39 FR 33103), the agency suggested that

the conditions included in the monograph (Category I) be effective 30

days after the date of publication of the final monograph in the

Federal Register and that the conditions excluded from the monograph

(Category II) be eliminated from OTC drug products effective 6 months

after the date of publication of the final monograph, regardless of

whether further testing was undertaken to justify their future use.

Experience has shown that relabeling of products covered by the

monograph is necessary in order for manufacturers to comply with the

monograph. New labels containing the monograph labeling have to be

written, ordered, received, and incorporated into the manufacturing

process. The agency has determined that it is impractical to expect new

labeling to be in effect 30 days after the date of publication of the

final monograph. Experience has shown also that if the deadline for

relabeling is too short, the agency is burdened with extension requests

and related paperwork.

In addition, some products will have to be reformulated to comply

with the monograph. Reformulation often involves the need to do

stability testing on the new product. An accelerated aging process may

be used to test a new formulation; however, if the stability testing is

not successful, and if further reformulation is required, there could

be a further delay in having a new product available for manufacture.

The agency wishes to establish a reasonable period of time for

relabeling and reformulation in order to avoid an unnecessary

disruption of the marketplace that could not only result in economic

loss, but also interfere with consumers' access to safe and effective

drug products. Therefore, the agency is proposing that the final

monograph be effective 12 months after the date of its publication in

the Federal Register. The agency believes that within 12 months after

the date of publication most manufacturers can order new labeling and

reformulate their products and have them in compliance in the

marketplace. If the agency determines that any labeling for a condition

included in the final monograph should be implemented sooner than the

12-month effective date, a shorter deadline may be established.

Similarly, if a safety problem is identified for a particular

nonmonograph condition, a shorter deadline may be set for removal of

that condition from OTC drug products.

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 January 7, 1972 (37 FR 235)

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 (address

above).

I. The Agency's Tentative Conclusions on the Comments and Reply

Comments

A. General Comments

1. Two comments contended that OTC drug monographs are

interpretive, as opposed to substantive, regulations. One 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 to 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 pointed out that under ``Subpart B--Active

Ingredients'' of the tentative final monograph, no CFR part number was

assigned to the category ``skin antiseptic.'' However, part numbers

were assigned to other categories without any Category I ingredients,

with the term ``reserved'' in parentheses. The comment requested that

this omission be corrected in the amended tentative final monograph.

The omission pointed out by the comment was an oversight. However,

it is no longer necessary to assign a CFR part number to the category

``skin antiseptic,'' because skin antiseptics have been included in

broader categories identified as first aid antiseptics in the amended

tentative final monograph for first aid antiseptics (56 FR 33644) and

as health-care antiseptics in this tentative final monograph. (See

section I.B., comment 3.) All Category I first aid antiseptic and

health-care antiseptic active ingredients have been listed in the

amended tentative final monograph under subpart A and subpart E,

respectively.

B. General Comments on Antimicrobials

3. A number of comments objected to the Panel's recommendation for

separate statements of identity in the labeling of products containing

the same antimicrobial active ingredient. As an example, several

comments noted that povidone-iodine has several professional uses

(health-care personnel handwash, skin antiseptic, and surgical hand

scrub) and marketing a product in conformance with two or more product

categories becomes difficult because there are different labeling

requirements for each drug product category. Some comments requested

FDA to combine the drug product category designations or to add a new

multipurpose product category that allows the combining of labeling

indications now included in several product categories. One comment

specifically recommended that the agency consider changing product

class designations and/or adding a new product class ``Multi Purpose

Skin Prep'' or ``Skin Prep,'' with the indications for use including

those listed under Sec. 333.85 (health-care personnel hand wash),

Sec. 333.87 (patient preoperative skin preparation), Sec. 333.90 (skin

antiseptic), and Sec. 333.97 (surgical hand scrub).

Another comment stated that the word ``skin'' was superfluous

because all OTC antiseptics are intended only for use on the skin;

still another comment contended that the statement of identity

``antiseptic'' is preferable to ``skin antiseptic'' because these

products are used on cuts, scratches, and mucous membranes as well as

skin.

In response to the advance notice of proposed rulemaking and

reopening of the administrative record for alcohol drug products for

topical antimicrobial OTC use published in the Federal Register of May

21, 1982 (47 FR 22324), one comment objected to the statement of

identity in proposed Sec. 333.98(a) which read, ``alcohol for topical

antimicrobial use,'' (47 FR 22324 at 22332). The comment stated that

this term would be confusing to the consumer and suggested the term

``antiseptic for the skin.''

The agency agrees that OTC topical antimicrobial drug products need

not have multiple statements of identity. In reviewing the statements

of identity recommended by the Antimicrobial I Panel (39 FR 33103),

i.e., health-care personnel handwash, patient preoperative skin

preparation, skin antiseptic, surgical hand scrub, and the statement of

identity recommended by the Miscellaneous External Panel (47 FR 22324),

i.e., alcohol for topical antimicrobial use, the agency has determined

that the general term ``antiseptic'' broadly describes all proposed

product categories and reflects the basic intended uses of these

products. The agency believes that the statement of identity of

``multiple purpose skin prep'' or ``skin prep'' recommended by one

comment would not as clearly and succinctly describe the use of these

products as the statement of identity ``antiseptic.'' As discussed in

section I.B., comment 5, the agency is also proposing an additional

term ``antiseptic handwash'' as a statement of identity to describe

products for home use.

As discussed in the first aid antiseptic segment of this rulemaking

(56 FR 33644 at 33647), the term ``skin'' has been deleted from the

previously proposed statement of identity ``skin antiseptic.'' Although

several comments felt that the word ``skin'' was superfluous, the

agency has no objection to the statement ``antiseptic for the skin'' or

``skin antiseptic'' appearing elsewhere in the labeling of these

products as additional information to the consumer or health-care

professional, provided it does not appear in any portion of the

labeling required by the monograph and does not detract from such

required information. (See section I.I., comment 19.)

As stated in the first aid antiseptic segment of this rulemaking

(56 FR 33644 at 33647), the agency believes that the term

``antiseptic'' is readily understood by consumers. The agency also

finds this to be true for health professionals. The agency is therefore

proposing the term ``antiseptic'' as the general statement of identity

for all OTC topical antimicrobial ingredients included in this

tentative final monograph. Further, FDA is also proposing that

manufacturers may have an option to provide an alternate statement of

identity describing only the specific intended use(s) of the product.

Specifically, the agency is proposing that the statement of identity

for antiseptic drug products in Sec. 333.450(a) read as follows: ``The

labeling of a single-use product contains the established name of the

drug, if any, and identifies the product as an `antiseptic' and/or with

the appropriate statement of identity described in Secs. 333.455(a),

333.460(a), or 333.465(a). The labeling of a multiple-use product

contains the established name of the drug, if any, and may use the

single statement of identity `antiseptic' and/or the appropriate

statements of identity described in Secs. 333.455(a), 333.460(a), and

333.465(a). When `antiseptic' is used as the only statement of identity

on a single-use or a multiple-use product, the intended use(s), such as

patient preoperative skin preparation, is to be included under the

indications. For multiple-use products, a statement of the intended use

should also precede the specific directions for each use.''

The agency believes that the proposed labeling for these multiple-

use products is flexible and provides manufacturers with a number of

options. However, the agency recognizes that some manufacturers may

wish to label their antiseptic drug products with all of the allowable

indications for a particular active ingredient and that this may give

rise to difficulties in incorporating all of the information on a

product's various uses in the limited space on an OTC label. The agency

wishes to point out that some portions of the proposed indications are

optional, i.e., the examples included in both the antiseptic and

health-care personnel handwash indications, and need not be

incorporated in the labeling at all. In addition, manufacturers are

free to design ways of incorporating all the information on the various

uses of their drug product through the use of flap labels, redesigned

packages, or package inserts.

The agency is providing several examples of labeling for an

antiseptic product containing povidone-iodine when labeled as a single-

use or as a multiple-use product, as follows:

1. When labeled as a single-use product, i.e., patient preoperative

skin preparation.

a. Established name: povidone-iodine.

b. Statement of identity (any of these is acceptable):

(1) ``antiseptic'';

(2) ``patient preoperative skin preparation'';

(3) ``antiseptic/patient preoperative skin preparation.''

c. Indications:

(1) When only ``antiseptic'' is used in the statement of identity:

``Patient preoperative skin preparation:

Helps to reduce bacteria that potentially can cause skin

infection.''

(2) When patient preoperative skin preparation is used as or

included as part of the statement of identity: ``Helps to reduce

bacteria that potentially can cause skin infection.''

d. Directions: (Insert directions in Sec. 333.460(d).)

2. When labeled as a multiple-use product, i.e., patient

preoperative skin preparation, antiseptic handwash or health-care

personnel handwash, and surgical hand scrub.

a. Established name: povidone-iodine.

b. Statement of identity (any of these is acceptable):

(1) ``antiseptic'';

(2) ``patient preoperative skin preparation, antiseptic handwash or

health-care personnel handwash, and surgical hand scrub'';

(3) ``antiseptic/patient preoperative skin preparation, antiseptic

handwash or health-care personnel handwash, and surgical hand scrub.''

c. Indications: Irrespective of which statement of identity is

used, the following is required: ``Patient preoperative skin

preparation: Helps to reduce bacteria that potentially can cause skin

infection. Antiseptic handwash: For handwashing to reduce bacteria on

the skin (which may be followed by one or more of the following: after

changing diapers, after assisting ill persons, or before contact with a

person under medical care or treatment). Health-care personnel

handwash: Handwash to help reduce bacteria that potentially can cause

disease or For handwashing to reduce bacteria on the skin (which may be

followed by one or more of the following: after changing diapers, after

assisting ill persons, or before contact with a person under medical

care or treatment). Surgical hand scrub: Significantly reduces the

number of micro-organisms on the hands and forearms prior to surgery or

patient care.''

d. Directions: The following is required: Patient preoperative skin

preparation: (Insert directions in Sec. 333.460(d).) Antiseptic

handwash or health-care personnel handwash: (Insert directions in

Sec. 333.455(c).) Surgical handscrub: (Insert directions in

Sec. 333.465(c).)

4. One comment requested that scrubbing devices such as brushes or

sponges that are impregnated with approved antimicrobial ingredients be

included in the monograph. Another comment requested clarification of

the agency's views on trays or kits that contain povidone-iodine and

disposable instruments (scissors, forceps, and hemostats) packed in a

sterile package, which are designed to reduce the incidence of cross-

infection in hospitals.

This tentative final monograph does not provide for the use of

devices such as brushes or sponges impregnated with antimicrobials, or

of trays or kits that contain povidone-iodine and disposable

instruments, because the monograph is intended to regulate only OTC

drug active ingredients. Since these comments were submitted, the

agency has established procedures (see 21 CFR part 3) describing how it

determines which agency component has primary jurisdiction for the

premarket review and regulation of products comprised of any

combination of a drug and a device. In addition, interested parties are

encouraged to read the following document (Ref. 1) for guidance:

``Intercenter Agreement Between the Center for Drug Evaluation and

Research and the Center for Devices and Radiological Health.'' (See

Sec. 3.5 (21 CFR 3.5).) This agreement is on file in the Dockets

Management Branch (address above).

(1) Intercenter Agreement Between the Center for Drug Evaluation

and Research and the Center for Devices and Radiological Health in OTC

Vol. 230001, Docket No. 75N-183H, Dockets Management Branch.

5. One comment expressed concern that the tentative final monograph

failed to provide consumers with an antibacterial skin cleanser for

home use. The comment noted that, in addition to professional health

care personnel, many consumers have a need for cleansing products

containing antibacterial agents for the purpose of promoting good

individual and family hygiene. Uses for such products include the

following: (1) To reduce bacteria on the hands and face to a greater

extent than can be accomplished with ordinary soap, and to prevent

accumulation of bacteria from potential sources of contamination. The

following examples were cited: Cleansing oneself after changing a

baby's diaper, or after assisting aged or ill members of the household

with their toilet needs, and before preparing a family meal. (2) The

added benefit of an antibacterial cleanser for the minute cuts and

abrasions from shaving and other minor traumas. (3) The need for an

antibacterial cleanser other than bar soap on local parts of the body

such as the face because soap (alkali salts of fatty acids) can be

irritating or too drying for some individuals' needs. The comment

recommended a new product class under proposed Sec. 333.90(a) (skin

antiseptic) to be identified as ``Antimicrobial (or Antibacterial)

Personal Cleanser'' with claims such as ``decreases bacteria on the

skin'' and ``contains an antibacterial agent.'' The comment also

suggested that the 10-day maximum use limitation would not be

appropriate for this product class, but use could be restricted to 5 or

10 times daily.

Another comment recommended that antimicrobial soaps be allowed to

make claims relating to general health care and personal hygiene

similar to the claims allowed for health-care personnel handwashes. The

comment stated that an antimicrobial soap will reduce bacteria or the

transfer of potentially pathogenic micro-organisms in the home and,

therefore, serves as a preventive health care aid in controlling

diseases.

A third comment requested the addition of a fourth indication for

alcohol active ingredients in proposed Sec. 333.98(b) to allow use as

an antibacterial handwash to avoid cross-contamination from one

individual to another. The comment argued that products containing

alcohols are often used as handwashes by athletic trainers to help

prevent the spread of skin infections from one individual to another in

situations in which soap and water are not available, e.g., on the

playing field.

A fourth comment asserted that numerous other meaningful and

truthful indications can be used which enhance the safe and effective

use of a health-care personnel handwash. For example, the terms

``microbicidal cleanser'' or ``antiseptic germicidal skin cleanser''

are appropriate and meaningful terminology describing this use

indication.

The agency agrees that antibacterial or antiseptic personal

cleanser products are practical for home use, to help prevent cross

contamination from one person to another, especially after diaper

changing and caring for invalids or ill family members. The agency also

agrees with one comment that claims relating to general health-care and

personal hygiene similar to the claims allowed for health-care

personnel handwashes may be suitable because such claims explain the

uses of these products in lay terms.

In the Federal Register of July 22, 1991 (56 FR 33644), the agency

separated the first aid antiseptic uses of OTC topical antimicrobial

drug products from the ``non-first aid uses.'' In that document, the

agency proposed that the following terms and categories be deleted:

skin antiseptics, skin wound protectants, and skin wound cleansers; and

the agency proposed that the appropriate labeling, instead, be included

in a new category called ``first aid antiseptics'' (56 FR 33644 at

33649). Several uses proposed by one comment, i.e., ``minute cuts and

abrasions from shaving and other minor traumas,'' are considered as

describing ``first aid uses'' and are adequately covered by the

labeling provided for ``first aid antiseptics'' in proposed

Sec. 333.50(b) (56 FR 33677), which contains the following: ``First aid

to help'' (select one of the following: ``prevent,'' (``decrease''

(``the risk of'' or ``the chance of'')), (``reduce'' (``the risk of''

or ``the chance of'')), ``guard against,'' or ``protect against'')

(select one of the following: ``infection,'' ``bacterial

contamination,'' or ``skin infection'') ``in minor cuts, scrapes, and

burns.'' The agency believes that the first aid indication is

sufficiently broad to cover minute cuts and abrasions from shaving and

that it is not necessary to include the words ``other minor traumas''

in the indications statement.

Beyond the first aid uses described in the first comment, the

agency recognizes a need for an OTC ``antiseptic handwash'' product for

repeated or daily use over an extended period of time for some of the

other uses described by the comment. The agency agrees with the

comments that health-care personnel handwashes are appropriate for such

use because submitted data from effectiveness studies, for uses subject

to this rulemaking, were derived from handwashing tests similar to or

the same as tests described in the agency's previously proposed testing

guidelines (see 43 FR 1210 at 1240), i.e., ``Modified Cade Procedure,''

``Glove Juice Test,'' and ``Test for Health-Care Personnel Handwash

Effectiveness.'' The agency is proposing in this tentative final

monograph in Sec. 333.455(a) that a health-care personnel handwash can

also bear a statement of identity of ``antiseptic handwash.'' (See

section I.B., comment 3.) For products labeled for multiple uses

including both antiseptic handwash and first aid labeling claims, the

general statement of identity would be ``antiseptic'' as described in

section I.B., comment 3. The product would then need to incorporate the

monograph labeling for both antiseptic handwash as well as first aid

antiseptic.

The term ``cleanser'' included in claims requested by the comments

is not appropriate in this rulemaking because it is considered to be a

cosmetic claim in view of the fact that the Federal Food, Drug, and

Cosmetic Act (the act) defines a cosmetic as ``articles intended to be

* * * applied to the human body * * * for cleansing * * *'' (21 U.S.C.

321(i)(1)) and thus may be misleading to consumers. As discussed in

section I.I., comment 19, the terms ``microbicidal'' and ``germicidal''

may appear in the labeling of OTC antiseptic drug products under

certain conditions.

Accordingly, the agency is proposing as the indication for products

bearing the statement of identity ``antiseptic handwash'' a general

claim similar to one recommended by one of the comments, i.e., ``for

handwashing to decrease bacteria on the skin.'' The agency has

determined that this claim may, at the manufacturer's option, be

followed by one or more of the following examples: ``after changing

diapers,'' ``after assisting ill persons,'' or ``before contact with a

person under medical care or treatment.''

Descriptive statements such as ``contains antibacterial

ingredients'' and ``for the purpose of promoting good individual and

family hygiene'' are considered to be examples of statements not

significantly related to the safe and effective use of the product and

thus are outside the scope of the rulemaking. Such statements may be

included in the labeling of these OTC drug products subject to the

statutory provisions against false or misleading labeling.

The agency has determined that the indication proposed for

antiseptic handwash drug products is also appropriate for health-care

personnel handwashes and is also proposing the following indication for

health-care personnel handwashes. ``For handwashing to decrease

bacteria on the skin'' (which may be followed by one or more of the

following: ``after changing diapers,'' ``after assisting ill persons,''

or ``before contact with a person under medical care or treatment.'')

In addition to the indication proposed above, the agency is proposing

that health-care personnel handwashes may also bear the following

indication: ``Handwash to help reduce bacteria that potentially can

cause disease.'' The agency is proposing the statement ``recommended

for repeated use'' as an ``other allowable indication'' for antiseptic

or health-care personnel handwash drug products (see below).

The agency sees no reason to continue to include ``antimicrobial

soap'' as a separate product category. Soap is considered to be a

dosage form, and specific dosage forms are not being included in the

monograph unless there is a particular safety or efficacy reason for

doing so. Antimicrobial ingredients may be formulated as soaps for some

of the uses discussed in this document, e.g., handwash; however, the

designation ``antimicrobial soap'' is no longer being proposed for

inclusion in the monograph. In addition, the agency considers the other

product categories that are being proposed to be more informative to

the users of these products.

Based upon the comments, the agency is proposing labeling

appropriate for professional or consumer uses as follows:

Section 333.455 Labeling of Antiseptic Handwash or Health-Care

Personnel Handwash Drug Products.

(a) Statement of identity. The labeling of the product contains the

established name of the drug, if any, and identifies the product as an

``antiseptic,'' as stated above under Sec. 333.450(a), and/or

``antiseptic handwash,'' or ``health-care personnel handwash.''

(b) Indications. * * *

(1) For products labeled as a health-care personnel handwash.

``Handwash to help reduce bacteria that potentially can cause disease''

or ``For handwashing to decrease bacteria on the skin'' (which may be

followed by one or more of the following: ``after changing diapers,''

``after assisting ill persons,'' or ``before contact with a person

under medical care or treatment.'')

(2) For products labeled as an antiseptic handwash. ``For

handwashing to decrease bacteria on the skin'' (which may be followed

by one or more of the following: ``after changing diapers,'' ``after

assisting ill persons,'' or ``before contact with a person under

medical care or treatment.'')

(3) Other allowable indications for products labeled as either

antiseptic or health-care personnel handwash. The labeling of the

product may also contain the following phrase: ``Recommended for

repeated use.''

Other labeling claims requested by the comments for first aid

antiseptics are not being included in the tentative final monograph.

The agency believes that the general claim ``for handwashing to

decrease bacteria on the skin'' encompasses the variety of uses for

promoting good individual and family hygiene. The agency tentatively

concludes that the labeling statements proposed above express the same

concepts as the labeling suggested by the comments in language that can

be more readily understood by the consumer.

C. Comments on Definitions

6. One comment objected to a portion of the definition for health-

care personnel handwash in Sec. 333.3(d) of the tentative final

monograph that states that the antimicrobial agent is ``broad-

spectrum'' and ``if possible, persistent.'' The comment argued that,

because these handwashes are used 50 to 100 times daily, persistence of

effect is unnecessary. The comment also questioned the need for a

broad-spectrum antimicrobial, stating that Staphylococcus epidermidis

(S. epidermidis) generally is the only natural resident bacteria on the

skin, and other transient micro-organisms are more likely to be removed

mechanically by washing than by antimicrobial action. The comment

suggested that the choice to use or not to use a broad-spectrum

antimicrobial ingredient should be left to the manufacturer.

Another comment pointed out that the requirement for ``broad

spectrum'' activity is inconsistently applied in the definitions for

health-care personnel handwash, patient preoperative skin preparation,

and surgical hand scrub (Sec. 333.3(d), (e), and (i), respectively)

because ``broad spectrum'' activity is mandatory for the first two

classes and only ``desirable'' for surgical hand scrubs. The comment

cited comment 93 (43 FR 1210 at 1224) and the testing guidelines for

safety and effectiveness of OTC topical antimicrobials (43 FR 1239) to

show the agency's awareness of possible shifts in microbial flora due

to a lack of broad spectrum activity. The comment urged that all three

product classes include the requirement for each product to at least

demonstrate in vitro ``cidal'' activity against gram-negative bacteria,

fungi, and lipophilic and hydrophilic viruses in addition to the gram-

positive activity.

In Sec. 333.3(d) of the previous tentative final monograph, a

health-care personnel handwash was defined as an ``* * * antimicrobial-

containing preparation designed for frequent use; it reduces the number

of transient micro-organisms on intact skin to an initial baseline

level after adequate washing, rinsing, and drying, and it is broad-

spectrum, fast acting, and, if possible, persistent.'' In the tentative

final monograph, the agency agreed with the Panel that persistence,

defined as prolonged activity, is a valuable attribute that assures

antimicrobial activity during the interval between washings and is

important to a safe and effective health-care personnel handwash (43 FR

1215). The Panel explained that a property such as persistence, which

acts to prevent the growth or establishment of transient micro-

organisms as part of the normal baseline or resident flora, would be an

added benefit (39 FR 33103 at 33115). Although the Panel did not

propose persistence as a mandatory requirement for a health-care

personnel handwash, the agency is retaining the words ``if possible,

persistent'' in the definition in this amended tentative final

monograph because this is a desirable trait for these products.

Regarding the comment's objection to the broad-spectrum

requirement, the Panel in its discussion of the normal skin flora

stated that the predominant members of the normal flora are gram

positive cocci and diptheroids and not S. epidermidis, as the comment

indicates. The Panel stated further that a small number of gram

negative species, such as coliforms and related micro-organisms, as

well as higher forms such as yeast may also be residents of the skin of

healthy individuals (39 FR 33103 at 33107). In its discussion of

health-care personnel handwash drug products, the Panel acknowledged

that, in all likelihood, the specified effect of these products (i.e.,

removal of transient micro-organisms) can be achieved with a well

formulated nonantimicrobial soap or detergent product. However, the

Panel concluded that transient micro-organisms may become part of the

established ``resident'' flora with time, and stated that in a health-

care situation, the fast, effective removal of transient micro-

organisms is a requirement because they may be pathogenic (39 FR 33103

at 33115). The Panel recommended that health-care personnel handwash

drug products containing an antimicrobial ingredient should be broad

spectrum. The Panel defined ``broad spectrum'' in reference to

microbiological activity as meaning the antimicrobial has activity

against more than one type of micro-organism, that is, activity against

gram positive and gram negative bacteria, fungi, and viruses (39 FR

33115). Because transient micro-organisms present on the skin may

include widely diverse species, resulting from contact with

contaminated persons and materials, the agency concludes that a greater

reduction of transient micro-organisms on the skin can be achieved if

the antimicrobial containing drug product used as a health-care

personnel handwash provides broad spectrum activity.

In addition, because the principal intended use of these

professional use products is the prevention of nosocomial (hospital

acquired) infections, the agency believes that these drug products

should have demonstrable antimicrobial activity against a microbial

spectrum that includes the micro-organisms associated with these

infections. As discussed in section I.N., comment 28, the agency is

proposing, in Sec. 333.470(a)(1)(ii) of the testing requirements, a

list of micro-organisms that reflects a spectrum of antimicrobial

activity pertinent to the intended use of these drug products and

against which the products must be tested. The agency is proposing the

following definition of broad spectrum activity in Sec. 333.403(b) of

this amended tentative final monograph: ``Broad spectrum activity. A

properly formulated drug product, containing an ingredient included in

the monograph, that possesses in vitro activity against the micro-

organisms listed in Sec. 333.470(a)(1)(ii), as demonstrated by in vitro

minimum inhibitory concentration determinations conducted according to

methodology in Sec. 333.470(a)(1)(ii).'' This methodology has been

developed by the National Committee for Clinical Standards (NCCLS)

(Ref. 1). Although micro-organisms in addition to those listed may also

be used for testing, the agency will use the test micro-organisms

identified in Sec. 333.470(a)(1)(ii) for any necessary compliance

testing.

The agency wants to emphasize that in this amended tentative final

monograph the broad-spectrum criterion applies to final-formulated drug

products used as an antiseptic handwash or health-care personnel

handwash, patient preoperative skin preparation, and surgical hand

scrub. Although the Category I active ingredients currently included in

this amended tentative final monograph are broad spectrum independent

of formulation, some Category III antiseptic ingredients have limited

spectra (activity against only gram positive bacteria; for example,

chloroxylenol (see section I.G., comment 12) and triclosan (see section

I.L., comment 23)), but when properly formulated in a final product the

spectrum can be broadened to include additional activity against the

test micro-organisms, thereby possibly enabling these ingredients to

become Category I. Although the agency agrees with the first comment

that the manufacturer may use or not use a broad-spectrum ingredient in

a particular health-care antiseptic drug product, the finished product

must demonstrate in vitro activity against the specific micro-organisms

listed in proposed Sec. 333.470(a)(1)(ii).

In response to the second comment, that broad spectrum was

inconsistently applied in the definitions of the three product classes,

the agency has reevaluated the issue and believes that all product

classes should be broad spectrum. As stated in the tentative final

monograph (43 FR 1210 at 1212), maintaining the balance among species

of micro-organisms constituting the normal skin flora is more likely to

be threatened by use of antimicrobial products with a limited spectrum.

Also much of the data concerning the spread of infections in hospitals

indicates that the use of an antimicrobial with broad spectrum activity

would help prevent this (see section I.D., comment 9). Based on the

reasons mentioned above, the agency is proposing to include ``broad

spectrum'' in the definitions of the three product classes included in

this tentative final monograph.

Reference

(1) National Committee for Clinical Laboratory Standards,

``Methods for Dilution Antimicrobial Susceptibility Tests for

Bacteria that Grow Aerobically--2d ed.; Approved Standard,'' NCCLS

Document M7-A2, 10:8, 1990.

D. Comments on Labeling

7. Several comments contended that FDA does not have the authority

to restrict OTC labeling claims to exact wording, to the exclusion of

what the comments described as other ``equally truthful claims for the

products.'' One comment pointed out that numerous other meaningful and

truthful statements will provide useful information and will enhance

the safe and effective use of these products. Several comments

maintained that manufacturers have a constitutional right to use any

truthful, nonmisleading labeling under the first amendment. To support

their position, the comments cited Bigelow v. Virginia, 421 U.S. 809

(1975); Virginia State Board of Pharmacy v. Virginia Citizens Consumer

Council, Inc., 425 U.S. 748 (1976); Linmark Associates, Inc. v.

Willingboro, 431 U.S. 85 (1977); Bates v. State Bar of Arizona, 433

U.S. 350 (1977); Federal Trade Commission v. Beneficial Corp., 542 F.2d

611, 97 S. Ct. 1679 (1977); and Warner-Lambert Co. v. Federal Trade

Commission, 562 F.2d 749 at 768 (D.C. Cir. 1977).

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 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., 21 CFR 201.63 or 330.1(g).

In the previous tentative final monograph, supplemental language

relating to indications had been proposed and captioned as Other

Allowable Statements in Secs. 333.85, 333.87 and 333.97. Under FDA's

revised labeling policy (51 FR 16258), such statements are included at

the tentative final stage as examples of other truthful and

nonmisleading language that would be allowed elsewhere in the labeling.

In accordance with the revised labeling policy, such statements would

not be included in a final monograph.

In preparing this amended tentative final monograph, the agency has

reevaluated these ``other allowable statements'' to determine whether

they should be incorporated, wherever possible, as part of the

indications developed under the monograph.

The agency has reviewed the ``Other Allowable Statements'' proposed

in the previous tentative final monograph in Sec. 333.85 for health-

care personnel handwash, in Sec. 333.87 for patient preoperative skin

preparation, and in Sec. 333.97 for surgical hand scrub. The statement

``recommended for repeated use'' proposed for a health-care personnel

handwash has been included in this amended tentative final monograph as

an ``other allowable indication'' in proposed Sec. 333.455 for

antiseptic handwash or health-care personnel handwash drug products.

(See section I.B., comment 5.)

The terms ``broad spectrum'' and ``fast-acting'' (if applicable)

were proposed as ``Other Allowable Statements'' for all three of these

product classes in the previous tentative final monograph. As discussed

in section I.C., comment 6, the agency is proposing to include ``broad

spectrum'' in the definition of the three product classes included in

this amended tentative final monograph. Although the term ``broad

spectrum'' is included in the definitions of these product classes, the

agency does not see a need to include this information in the

``indications'' for these products. Likewise, the term ``fast-acting''

is included in the definitions of these product classes, but the agency

does not see a need to include this information in the indications for

these products. This type of information may appear elsewhere in the

labeling of these products as additional information to the health-care

professional, provided it does not appear in any portion of the

labeling required by the monograph and does not detract from such

required information. Other previously proposed ``Other Allowable

Statements,'' i.e., ``contains antibacterial ingredient(s),''

``contains antimicrobial ingredient(s),'' and ``nonirritating,'' are

not related in a significant way to the safe and effective use of these

products. The agency does not believe that statements such as

``contains antibacterial ingredient(s)'' or ``contains antimicrobial

ingredient(s)'' are necessary on products intended primarily for health

professionals, but has no objection to such statements appearing in the

labeling as other information not intertwined with any portion of the

labeling required by the monograph. Likewise, the term

``nonirritating'' may appear as additional information to the health-

care professional, provided it does not appear in any portion of the

labeling required by the monograph and does not detract from such

required information. However, such statements are subject to the

provisions of section 502 of the act (21 U.S.C. 352) relating to

labeling that is false or misleading. Such statements will be evaluated

on a product-by- product basis, under the provisions of section 502 of

the act relating to labeling that is false or misleading.

8. Several comments requested that certain warnings required in the

labeling of OTC drug products marketed for the general public should

not be required on such products distributed only to health

professionals and labeled primarily for use in health-care facilities

as in proposed Sec. 333.99 ``Professional labeling'' (43 FR 1210 at

1248 and 1249). Examples cited were the cautionary statements for

``skin antiseptic'' and ``skin wound protectant'' in proposed

Secs. 333.90(c)(3) and 333.93(c)(3) ``Do not use this product for more

than 10 days. If the infection (condition) worsens or persists, see

your physician,'' and for ``skin wound protectant'' in proposed

Sec. 333.93(c)(7) ``Do not use on chronic skin conditions such as leg

ulcers, diaper rash, or hand eczema.'' The comments stated that the

professional use of these products sometimes differs from consumer use

and that products which are marketed only to health-care institutions

and are dispensed and administered by professionals should only contain

warnings that apply to professional use. One comment concluded that

requiring professional labeling to contain a caution such as in

proposed Sec. 333.93(c)(7) could possibly subject the health-care

facility and the physician to unwarranted product liability claims,

although the particular use of the product under medical supervision is

entirely justified and necessary for proper treatment of the patient.

One of the comments stated that flexibility should be provided so that

manufacturers can utilize only those warnings that are appropriate for

professional personnel when packages are restricted to health-care

facilities or where a topical antimicrobial product is used as part of

a course of treatment selected by the clinician.

In the Federal Register of November 12, 1973 (38 FR 31260), the

agency published the tentative final monograph for OTC antacid drug

products, in which the concept of ethical labeling for OTC drug

products was first discussed in comment 56 at 38 FR 31264. There, the

agency stated that the warning statements appearing on OTC drug

products should be included in ethical (professional) labeling.

Subsequently, in the previous tentative final monograph for OTC

topical antimicrobial drug products, published in the Federal Register

of January 6, 1978 (43 FR 1210), the agency proposed Sec. 333.99

(``Professional labeling'') which stated that the labeling of products

(covered by the monograph) that is provided only to health

professionals and the labeling for those products primarily used in

health-care facilities shall include all of the warnings required in

each subsection of the monograph, e.g., those in Sec. 333.90 for ``skin

antiseptic'' or Sec. 333.93 for ``skin wound protectant.''

As described in the first aid antiseptic segment of the tentative

final monograph for OTC antimicrobial drug products, published in the

Federal Register of July 22, 1991 (56 FR 33644), the agency has

proposed deletion of the categories cited by the comments, i.e., ``skin

antiseptic'' and ``skin wound protectant,'' as separate drug categories

and included them in a single drug product category identified as

``first aid antiseptic.'' The cautionary statements referred to by the

comments are addressed in that document.

In this document, the agency is addressing the uses other than

first-aid, i.e., health-care antiseptic uses, of topical antimicrobial

drug products. These products may contain the same antiseptic active

ingredient(s) as the first aid antiseptic drug products, but they are

labeled and marketed for different uses. The cautionary statements

previously proposed in Secs. 333.90(c)(3) and 333.93(c)(3) addressed

short-term first aid uses of products primarily proposed as ``consumer

products.'' These products were not principally intended to be marketed

for hospital or professional use. Therefore, the agency agrees with the

comments that such cautionary statements do not apply to professional

use of antiseptic drug products and need not appear in the labeling of

antiseptic products marketed as antiseptic handwashes or health-care

personnel handwashes, patient preoperative skin preparations, and

surgical hand scrubs. Likewise the agency believes that health-care

antiseptic drug products, marketed principally to health-care

professionals, do not need to bear a cautionary statement not to use

the product on chronic skin conditions such as leg ulcers, diaper rash,

or hand eczema. As the comment pointed out, professional use of these

products is different than consumer use and, in some instances, use of

the product on the above-mentioned skin conditions under medical

supervision may be justified and necessary for proper treatment of the

patient. Therefore, this cautionary statement is not being included in

this tentative final monograph.

This tentative final monograph addresses specifically the use of

these topical antiseptic drug products by health-care professionals and

in health-care facilities. The labeling proposed for those products in

this document represents that labeling which the agency believes

health-care professionals need to properly use these products.

Therefore, the agency believes that the warnings proposed in

Sec. 333.450(c) of this tentative final monograph should appear in the

labeling of these products that are directed to health-care

professionals and health-care facilities, even if the product is

marketed principally to these sources only. However, the agency

believes that one of these warnings can be modified if the product is

labeled ``For Hospital and Professional Use Only.'' In such cases, the

second sentence of the warning proposed in Sec. 333.450(c)(3),

regarding consulting a doctor, can be deleted. This concept is being

included in this tentative final monograph. (See Sec. 333.450(d).)

In responding to the comments regarding the warnings in the

``Professional labeling'' section (Sec. 333.99) of the previous

tentative final monograph, the agency has determined that these

warnings are no longer necessary. Accordingly, Sec. 333.99 is not being

included in this amended tentative final monograph. (See section I.D.,

comment 9 for discussion of Sec. 333.99(a), and section I.J., comment

21 for discussion of Sec. 333.99(b). Also, see section II.B., paragraph

14 in the first aid antiseptic segment of this tentative final

monograph (56 FR 33644 at 33675) for discussion of Sec. 333.99(c).)

9. Several comments made recommendations regarding the requirement

that professional labeling for all classes of OTC topical antimicrobial

drug products must contain the caution statement in proposed

Sec. 333.99(a), ``Caution: Overuse of this and other antimicrobial

products may result in an overgrowth of gram-negative micro-organisms,

particularly Pseudomonas.'' Some of the comments stated that this

caution statement should be required only for antimicrobials where

there is valid scientific evidence to show that such caution is

appropriate, for example, quaternary ammonium compounds and triclosan,

which have been associated with the overgrowth of gram-negative micro-

organisms, specifically Pseudomonas. Three comments contended that

reports of contamination of benzalkonium chloride solutions with

Pseudomonas and Enterobacteria species were basically the result of

misuse, improper storage and dilution, poor technique, and

contamination with neutralizing chemicals. One comment recommended that

the proposed caution statement in Sec. 333.99(a) should be changed to

read: ``Improper use or overuse * * *.'' and cited the discussion of

the proposed warning for quaternary ammonium compounds by the agency at

43 FR 1237 where the phrase ``misuse or overuse'' was included. Another

comment objected to the caution, arguing that it is based on

theoretical considerations only and there is no published clinical

evidence implicating quaternary ammonium compounds. Still another

comment stated that its quaternary ammonium compound product passed the

commonly used test for Pseudomonas activity.

In defense of triclosan's implication in Pseudomonas overgrowth,

one comment argued that overgrowth was just an unproven hypothesis and

submitted the ``Summary for Basis of Approval'' from an approved new

drug application (NDA) for chlorhexidine gluconate (Ref. 1) which

included data on a skin flora study that indicated an increasing,

continuous gram-negative growth only in the axillary area over a 6-

month period, even though chlorhexidine is active against gram-negative

micro-organisms. The comment referred to FDA's Division of Anti-

Infective Drug Products as having recognized that gram-negative

overgrowth can be adequately controlled by restricting use to

indications provided in the labeling of a product.

Several comments pointed out that data on povidone-iodine have

proven broad spectrum effectiveness, referring to the Centers for

Disease Control and Prevention's (CDC) recommendation (Ref. 2) for

using this ingredient for skin preparation before intravenous catheter

insertion and other procedures to reduce infection. The comments also

noted that in a study by Houang et al. (Ref. 3), in which 20 transfers

of 7 gram-negative micro-organisms (including Pseudomonas aeruginosa

(P. aeruginosa)) were made, the minimum inhibitory concentration did

not change, supporting the fact that repeated use of povidone-iodine

would not result in resistant micro-organisms. For these reasons, these

comments recommended that Sec. 333.99(a) should be revised to exclude

povidone-iodine.

After a thorough review and evaluation of the available data, the

agency concludes that the professional labeling caution that overuse of

an antimicrobial drug product may cause an overgrowth of gram-negative

micro-organisms is not necessary. In the previous tentative final

monograph (43 FR 1210 at 1212), the agency stated its awareness of the

theory that gram-negative bacteria will replace gram-positive bacteria

that are reduced in number or eliminated by use of antimicrobials and

encouraged research to test the validity of the theory. The agency also

recalled the Panel's highlighting the need for research on microbial

ecology of the skin and its concern about the effect of overuse of

antimicrobial drug products, especially products with a limited

spectrum, in hospitals and other closed populations. Therefore, the

agency proposed the professional labeling caution in Sec. 333.99(a)

``for certain antimicrobial ingredients approved for OTC drug use * * *

used in health-care facilities'' (43 FR 1213). However, the agency

concluded that the limited consumer use of these products in the

population at large did not constitute a risk that would warrant such a

label warning. Although benzalkonium chloride has been frequently

implicated in Pseudomonas hospital infections, the agency's review of

numerous reports and studies on quaternary ammonium compounds and other

antimicrobials (Refs. 4 through 10) indicates that specific causes for

contamination, such as lack of aseptic technique when applying

intravenous infusions and sterilization failure of the items used

(bottles, tubing, distilled water used in diluting benzalkonium

chloride), were the problem and not overuse of benzalkonium chloride.

The agency discussed this problem in the previous tentative final

monograph and stated that it appears that practices in the health-care

facility environments where quaternary ammonium compounds are commonly

used often fall short of the minimum necessary to prevent outbreaks of

infection. (See comment 51 43 FR 1210 at 1218.) Benzalkonium chloride

is more prone to become contaminated for several reasons that were

brought out in the studies: (1) Pseudomonas species are among the

bacteria most resistant to surface-active agents like quaternary

ammonium compounds. (2) The usual quaternary ammonium compound

concentration appears to be ineffective against some species, such as

Pseudomonas cepacia, an organism which has been reported to have been

associated with hospital infections. One study showed that this

organism survived 14 years in a salt solution preserved with 0.05

percent benzalkonium chloride. (3) Organic materials (gauze, cotton,

cork in stoppers, soaps), inorganic matter, protein, and anionic

substances inactivate quaternary ammonium compounds. (4) Hospital

personnel are unfamiliar with these problems and with procedures for

using quaternary ammonium compounds safely and effectively. Based on

these reports, the agency agrees with the comments that ``improper''

use, not ``overuse,'' is the cause of benzalkonium chloride being

implicated in Pseudomonas contamination and that there is a lack of

data demonstrating ``overuse'' to be the cause.

The agency also agrees with the comment which stated that it was an

unproven hypothesis that overuse of an antiseptic causes Pseudomonas

overgrowth. The ``Summary for Basis of Approval'' from an approved NDA

for chlorhexidine gluconate (Ref. 1) cites a skin flora study that

indicated that the axilla was an area where gram-negative micro-

organisms continued to be isolated even though chlorhexidine gluconate

has shown gram-negative effectiveness. The comment cited FDA's Division

of Anti-Infective Drug Products' recognition that for health-care uses,

such as surgical scrub and health-care personnel handwash, there would

be no problem with Pseudomonas overgrowth because the hands are an area

of the body not likely to support the growth of Pseudomonas because of

the lack of moisture. In defending triclosan, the comment contended

that this ingredient is bacteriostatic and does not eliminate all gram-

positive bacteria; therefore, it would not predispose for gram-negative

overgrowth. Triclosan has been implicated in Pseudomonas contamination

because it is primarily effective against gram-positive bacteria, has

limited in vitro and in vivo activity against gram-negative bacteria,

and no activity against Pseudomonas (43 FR 1210 at 1232). One report

showed that triclosan was effective against some gram-negative micro-

organisms, but not effective against Serratia and Pseudomonas (Ref.

11). Pseudomonas and Serratia resistance caused the contamination, not

overuse of the antiseptic.

The agency agrees with the comments that quaternary ammonium

compounds and triclosan have been implicated in Pseudomonas hospital

infections more frequently than povidone-iodine, but studies indicate

that `overuse' of these or any antimicrobial has not been the cause.

Pseudomonas species may become dominant because of inherent resistant

factors which enable them to survive the effects of many antibiotics

and antiseptics (Refs. 12, 13, and 14). In addition, this genus is

ubiquitous, found in both soil and water, and can multiply in almost

any moist environment with even a trace of organic material (Ref. 15).

The agency believes that the data and reports have not provided

specific evidence that repeated use of health-care antiseptics,

including benzalkonium chloride and triclosan, have brought about

overgrowth of gram-negative bacteria, particularly Pseudomonas. The

agency agrees with the comments that improper use, failure of hospital

personnel to use according to labeling indications, nonaseptic

technique in diluting and handling, and lack of good quality control to

ensure sterility of items in contact with antiseptics, such as sterile

distilled water, hosing, and receptacles, are responsible.

The study by Houang et al. (Ref. 3) shows that repeated in vitro

exposure of seven gram-negative micro-organisms, including P.

aeruginosa, in povidone-iodine dilutions did not result in the

development of resistance. The agency notes that CDC previously

recommended povidone-iodine for use in intravenous catheter and other

procedures (Ref. 2). However, there has been one report from CDC (Ref.

16) which described Pseudomonas hospital infections caused by

intrinsically contaminated povidone-iodine (contaminated during

manufacture, indicating failure of control of microbiological

contamination). Compliance with the agency's regulations governing

current good manufacturing practice for finished pharmaceuticals (21

CFR part 211) should prevent intrinsic contamination.

Accordingly, the agency concludes that a cautionary statement

against overuse is not needed in the professional labeling of health-

care antiseptic drug products. Therefore, the previously proposed

caution in Sec. 333.99(a) is not being included in this tentative final

monograph. If new information indicates a need for a cautionary

statement, the agency will consider appropriate action at that time.

References

(1) ``Summary for Basis of Approval, Chlorhexidine Gluconate,''

NDA 17-768, Comment No. SUP022, Docket No. 75N-0183, Dockets

Management Branch.

(2) ``Recommendations for the Insertion and Maintenance of

Plastic Intravenous Catheters,'' Paper for Training Purpose,

Hospital Infections and Microbiological Control Sections, Bacterial

Diseases Branch, Epidemiology Program, Centers for Disease Control,

1972.

(3) Houang, E.T. et al., ``Absence of Bacterial Resistance to

Povidone Iodine,'' Journal of Clinical Pathology, 29:752-755, 1976.

(4) Mitchell, R.G., and A.C. Hayward, ``Postoperative Urinary-

Tract Infections Caused by Contaminated Irrigating Fluid,'' The

Lancet, 1:793-795, 1966.

(5) Geftic, S.G., H. Heymann, and F. W. Adair, ``Fourteen-Year

Survival of Pseudomonas cepacia in a Salts Solution Preserved with

Benzalkonium Chloride.'' Applied and Environmental Microbiology,

37:505-510, 1979.

(6) Rapkin, R.H., ``Pseudomonas cepacia in an Intensive Care

Nursery,'' Pediatrics, 57:239-243, 1976.

(7) Plotkin, S.A., and R. Austrian, ``Bacteremia Caused by

Pseudomonas Sp. Following the Use of Materials Stored in Solutions

of a Cationic Surface-Active Agent,'' The American Journal of the

Medical Sciences, 235:621-627, 1958.

(8) Frank, M.J., and W. Schaffner, ``Contaminated Aqueous

Benzalkonium Chloride. An Unnecessary Hospital Infection Hazard,''

Journal of the American Medical Association, 236:2418-2419, 1976.

(9) Kaslow, R.A., D.C. Mackel, and G.F. Maillison, ``Nosocomial

Pseudobacteremia. Positive Blood Cultures Due to Contaminated

Benzalkonium Antiseptic,'' Journal of the American Medical

Association, 236:2407-2409, 1976.

(10) Burdon, D.W., and J.L. Whitby, ``Contamination of Hospital

Disinfectants with Pseudomonas Species,'' British Medical Journal,

2:153-155, 1967.

(11) Barry, M.A. et al., ``Serratia marcescens Contamination of

Antiseptic Soap Containing Triclosan: Implications for Nosocomial

Infection,'' Infection Control, 5:427-430, 1984.

(12) Dailey, R.H., and E.J. Benner, ``Necrotizing Pneumonitis

Due to the Pseudomonad `Eugonic Oxidizer-Group I','' New England

Journal of Medicine, 279:361-2, 1968.

(13) Weinstein, A.J. et al., ``Case Report: Pseudomonas cepacia

Pneumonia,'' American Journal of the Medical Sciences, 265:491-494,

1973.

(14) Richards, R.M.E., and J.M. Richards, ``Pseudomonas cepacia

Resistance to Antibacterials,'' Journal of Pharmaceutical Sciences,

68:1436-1438, 1979.

(15) Sonnenwirth, A.C., ``Pseudomonas,'' in ``Microbiology,'' 2d

ed., edited by Davis, B.D. et al, Harper and Row, Hagerstown, MD,

New York, Evanston, San Francisco, London, p. 783, 1973.

(16) ``Contaminated Povidone-Iodine Solution--Northeastern

United States,'' Morbidity and Mortality Weekly Report, Public

Health Service, Centers for Disease Control, HHS Publication No.

(CDC) 81-8017, 29:553-555, 1980.

E. Comment on Alcohol

10. One comment submitted data on the safety and effectiveness of

62 percent alcohol formulated in an emolliented vehicle and dispensed

as a foam (Ref. 1) and requested that alcohol be included in the

topical antimicrobial monograph as a surgical hand scrub, health-care

personnel handwash, and hand degermer.

Data on the safety and effectiveness of alcohol formulated in an

emolliented vehicle for use as a surgical hand scrub, health-care

personnel handwash, and hand degermer were submitted to the

Miscellaneous External Panel (Refs. 2 and 3). However, the data were

not reviewed or categorized for these uses during that rulemaking. In

reviewing alcohol for short-term uses, that Panel stated, ``ethyl

alcohol acts relatively quickly to decrease the number of micro-

organisms on the skin surface. Each minute that scrubbed hands and arms

were immersed in approximately 77 percent ethyl alcohol by volume was

found to be equivalent to 6.5 minutes of scrubbing in water; if the

skin was scrubbed with the alcohol, the rate was further increased''

(47 FR 22324 at 22328). The Panel found ethyl alcohol safe and

effective for use as a topical antimicrobial preparation in

concentrations of 60 to 95 percent by volume in an aqueous solution.

The following indications were proposed:

(1) ``For first aid use to decrease germs in minor cuts and

scrapes.''

(2) ``To decrease germs on the skin prior to removing a splinter or

other foreign object.''

(3) ``For preparation of the skin prior to an injection.'' (See the

advance notice of proposed rulemaking for OTC alcohol drug products for

topical antimicrobial use, in the Federal Register of May 21, 1982, 47

FR 22324.)

The submissions (Refs. 1 and 2) included effectiveness data and

labeling for a currently marketed product containing 62 percent ethyl

alcohol formulated in an emolliented vehicle and dispensed as a foam

used ``* * * to degerm hands * * *.'' The agency has reviewed these

data, derived from effectiveness testing as a surgical hand scrub

(glove juice test) and health-care personnel handwash, and finds that

they meet the procedures in the testing guidelines in the previous

tentative final monograph (43 FR 1210 at 1242). Statistical analyses

showed microbial reduction to be highly significant. A glove juice test

showed that alcohol foam reduced the baseline number of bacteria

present in normal skin flora, after first use, by 1.87 logs, and, after

continued use for 5 days, by 2.36 logs. The reduction of the baseline

number of bacteria was maintained for up to 6 hours under surgical

gloves. A health-care personnel handwash effectiveness test showed

microbial reduction on test subjects' hands, artificially contaminated

with Serratia marcescens (S. marcescens). Microbial reduction averaged

3.3 logs after 5 treatments and 3.63 logs after 25 treatments. In vitro

data, derived from studies using S. marcescens as the test bacteria,

showed that alcohol properly formulated in an emolliented vehicle and

dispensed as a foam, significantly reduced the number of test bacteria,

in 10 percent serum, within 15 seconds.

Based on these data and the conclusions of the Miscellaneous

External Panel (47 FR 22324), the agency concludes that alcohol, when

properly formulated, is effective for use as a surgical hand scrub and

antiseptic handwash or health-care personnel handwash. Because it is

well established that alcohol alone does not provide persistence, the

agency notes that a preservative agent in the vehicle provided the

persistent effect to maintain reduction in the baseline number of

bacteria for 6 hours as required to demonstrate efficacy as a surgical

hand scrub drug product.

The agency is including alcohol in proposed Sec. 333.410(a)

(antiseptic handwash or health-care personnel handwash),

Sec. 333.412(a) (patient preoperative skin preparation), and

Sec. 333.414(a) (surgical hand scrub), as follows: ``Alcohol 60 to 95

percent by volume in an aqueous solution denatured according to Bureau

of Alcohol, Tobacco and Firearms regulations in 27 CFR part 20.''

Further, the agency finds the Miscellaneous External Panel's proposed

Category I indication for OTC alcohol drug products, i.e., ``for

preparation of the skin prior to an injection'' to be an appropriate

indication for patient preoperative skin preparation drug products.

Based on that Panel's recommendations, the agency is including this

indication as an additional claim for alcohol drug products in

Sec. 333.460(b)(2) of the proposed monograph. In addition, based on

that Panel's similar recommendations for isopropyl alcohol (47 FR 22324

at 22329 and 22332), the agency is proposing this indication for OTC

isopropyl alcohol drug products in Sec. 333.460(b)(3). As discussed in

section I.N., comment 28, the agency is proposing new effectiveness

criteria for drug products labeled for this use.

The monograph will also state that an alcohol drug product must be

properly formulated, such as the product in an emolliented vehicle

dispensed as a foam discussed above, to meet the test requirements in

Sec. 333.470. This means that alcohol when intended for certain uses

must be able to demonstrate effectiveness by certain tests proposed in

this tentative final monograph, as follows: (1) Antiseptic or health-

care personnel handwash--Sec. 333.470(b)(2), (2) patient preoperative

skin preparation--Sec. 333.470(b) (3), and (3) surgical hand scrub--

Sec. 333.470(b)(1). As discussed in section I.B., comment 5, the term

``antiseptic handwash'' in lieu of ``hand degermer'' is being proposed

in the monograph as the statement of identity for this type of product.

The labeling for the alcohol product (Ref. 1) provides directions

for use without water rinsing, where water is not readily available, as

follows: ``A `palmful' (5 grams) is dispensed in one hand. It is spread

on both hands and rubbed into the skin until dry (approximately 1 to 2

minutes). A smaller amount (2.5 grams) is then dispensed into one hand,

spread over both hands to wrist, and rubbed into the skin until dry

(approximately 30 seconds).'' The agency concurs with these directions

and is incorporating them into its proposed directions for use for OTC

topical antiseptic drug products, including alcohol, formulated for use

without water in this tentative final monograph. See proposed

Sec. 333.455(c) and Sec. 333.465(c).

References

(1) Unpublished studies on emolliented alcohol foam (62 percent

alcohol), Comments No. C105, C144, and CR7, Docket No. 75N-0183,

Dockets Management Branch.

(a) Microbiological evaluation of ``Alcare Hand Degermer'' on

personnel in a newborn intensive care unit, May 12, 1977.

(b) Results of a study of efficacy against experimental

contamination of human skin, June 20, 1978.

(c) Efficacy study with Vestal Foam results of a glove fluid

study, January 27, 1975.

(d) Serratia marcescens efficacy data for Alcare, February 20,

1978.

(e) Amended labeling for Alcare Foamed Alcohol, August 19, 1982.

(2) OTC Vol. 160377.

(3) OTC Vol. 160382.

F. Comments on Chlorhexidine Gluconate

11. Several comments requested that the agency include

chlorhexidine gluconate as a Category I ingredient in any amended

tentative final monograph. The comments submitted references and data

to establish general recognition of safety and effectiveness (Ref. 1),

and stated that chlorhexidine gluconate solution is recognized in the

``British Pharmacopeia'' (Ref. 2) and is formulated in a wide range of

products that have been successfully marketed to a material extent and

for a material length of time in other countries. The comments asserted

that when formulated in compliance with FDA's current good

manufacturing practice regulations (21 CFR part 211), chlorhexidine

products are safe and effective for use as skin wound cleansers, skin

wound protectants, patient preoperative skin preparations, skin

antiseptics, surgical hand scrubs, and health-care personnel

handwashes.

A reply comment argued that chlorhexidine gluconate, currently

marketed in the United States under approved new drug applications

(NDA's), is not eligible for an OTC drug monograph because the

ingredient has not been marketed within this country to a material

extent and for a material length of time. The comment added that

variations in final formulations may alter the safety and effectiveness

of the ingredient. The comment submitted data (Ref. 3) to support this

viewpoint and requested that chlorhexidine gluconate be classified in

Category II.

In the previous tentative final monograph (43 FR 1210),

chlorhexidine gluconate (4 percent solution) was neither addressed nor

categorized as Category I, II, or III. However, subsequent to the

tentative final monograph, the agency granted a petition (Ref. 4) and

in the Federal Register of March 9, 1979, reopened the administrative

record to allow interested persons an opportunity to submit data and

information (44 FR 13041). The comments (Ref. 1) and reply comment

(Ref. 2) were submitted in response to that notice. However, since that

time a majority of the comments on chlorhexidine submitted in response

to the notice have been withdrawn (Ref. 5). While the withdrawn

comments remain on public display as part of the administrative record,

they are no longer being considered in this rulemaking.

The agency has reviewed the marketing history of chlorhexidine

gluconate and finds that although it has been marketed for professional

or hospital use under NDA's, insufficient data remain in the public

administrative record for this rulemaking to support general

recognition of safety and effectiveness for OTC use. Accordingly,

chlorhexidine gluconate 4 percent aqueous solution as a health-care

antiseptic is a new drug and is not included in this tentative final

monograph.

References

(1) Comments No. C110, C116, C120, C130, C131, C136, C137,

EXT18, RC2, RC5, CP3, LET12, LET14, LET16, SUP30, SUP33, SUP38, and

SUP40, Docket No. 75N-0183, Dockets Management Branch.

(2) ``British Pharmacopeia,'' Vol. I, Her Majesty's Stationery

Office, London, pp. 100-101, 1980.

(3) Comments No. RC1 and RC4, Docket No. 75N-0183, Dockets

Management Branch.

(4) Comment No. CP3, Docket No. 75N-0183, Dockets Management

Branch.

(5) Comments No. WDL3, WDL4, and WDL5, Docket No. 75N-0183,

Dockets Management Branch.

G. Comments on Chloroxylenol

12. A number of comments disagreed with the agency's Category III

classification of chloroxylenol in the tentative final monograph. They

argued that a reevaluation of the data previously submitted to the

agency along with new data that have been submitted (Refs. 1 through

16) would provide adequate justification for classifying chloroxylenol

in Category I for safety and effectiveness for use in antimicrobial

soaps, health-care personnel handwashes, patient preoperative skin

preparations, skin antiseptics, skin wound cleansers, skin wound

protectants, and surgical hand scrubs. Several comments pointed out

that the Antimicrobial II Panel unanimously concluded that

chloroxylenol is generally recognized as safe for topical use in

athlete's foot and jock-itch preparations.

Based upon the submitted data (Refs. 1 through 16) and other

information reviewed by the Antimicrobial Panels, the agency concluded

in the amended tentative final monograph for OTC first aid antiseptic

drug products that chloroxylenol (0.24 percent to 3.75 percent) was

safe but not effective for short-term use as an OTC topical first aid

antiseptic (54 FR 33644 at 33658). These data (Refs. 1 through 16) and

new data submitted under the agency's ``feedback'' procedures (Refs. 17

through 30) are insufficient to support a Category I classification of

the safety and effectiveness of the ingredient for other long-term

uses, e.g., antiseptic handwash or health-care personnel handwash and

surgical hand scrub. The agency concludes that chloroxylenol remains

classified in Category III as an active ingredient for these uses.

However, the ingredient would be considered safe for short-term use as

a patient preoperative skin preparation but remains in Category III due

to a lack of effectiveness data for this use.

In the previous tentative final monograph (43 FR 1210 at 1222 and

1238), the agency stated that the data were insufficient to reclassify

chloroxylenol into Category I, and the ingredient remained in Category

III for safety and effectiveness. Indicating concern about the

absorption of topically applied antimicrobial drug products used

repeatedly by consumers over a number of years, the agency stated the

following regarding the safety of the ingredient:

Only the most superficial toxicity data in animals were

submitted to and reviewed by the Panel. The Commissioner concurs

with the Panel that toxicity in rodent and nonrodent species,

substantivity, blood levels, distribution and metabolism, as well as

any subsequent systemic absorption studies must be characterized * *

*. The degree of absorption of PCMX following topical administration

has not been established. The target organ for PCMX toxicity in

animals also remains unidentified and should be shown in a long-term

animal toxicity study.

While safety data (Refs. 1, 2, 6, and 7) are sufficient to

establish safety for short-term use such as for a patient preoperative

skin preparation drug product, these data do not resolve concerns about

long-term chronic toxicity. Conclusions on these data, which were also

reviewed by the Advisory Review Panel on OTC Antimicrobial II Drug

Products (Antimicrobial II Panel) in conjunction with its review of OTC

topical antifungal drug products, were published in the Federal

Register of March 23, 1982 (47 FR 12480). That Panel, which evaluated

the safety of the ingredient for use in OTC topical antifungal drug

products, categorized chloroxylenol (0.5 to 3.75 percent) as safe

(Category I) for short-term use (up to 13 weeks) and advised, ``* * *

relatively low doses of chloroxylenol can be systemically tolerated, at

least over a 13-week period. The Panel is concerned about the effect of

chronic administration on the liver, but does not consider that topical

application of chloroxylenol to small areas of the skin over short

periods of time would result in liver damage.'' (47 FR 12480 at 12534).

The agency subsequently agreed with the Panel's conclusions concerning

the safety of using the ingredient in OTC topical antifungal drug

products for the treatment of athlete's foot, jock itch, and ringworm

(maximum treatment duration 4 weeks) in its tentative final monograph

for these OTC drug products, published in the Federal Register of

December 12, 1989 (54 FR 51136 at 51139). The agency subsequently

finalized these conclusions in the final rule for OTC topical

antifungal drug products published in the Federal Register of September

23, 1993 (58 FR 49890).

Regarding long-term chronic toxicity, data and information provided

by one manufacturer included final reports of completed studies and

interim reports of incomplete studies (Ref. 2). The information also

contained a protocol of a planned preclinical study (projected starting

and completion dates for experiments) which identified a 2-year rat

feeding study. Because this study might resolve concerns about long-

term chronic toxicity, the agency requested the raw data (Ref. 31);

however, the manufacturer declined to submit the data, explaining that

it is no longer interested in marketing chloroxylenol, that its study

had not been completed, and that the study was conducted prior to

establishment of the Good Laboratory Practices regulations (Ref. 32).

In response to the agency's determination that data from a 2-year

rat feeding study were essential (Ref. 33), another manufacturer

submitted additional information along with copies of already available

safety data (Ref. 34). The manufacturer explained that it believes that

long-term safety data, i.e., 2-year oral feeding study, while not

currently available, may not be a necessity. Citing statements made by

the Panel, that its recommended guidelines for the safety testing of

these drug products were developed primarily for antimicrobial agents

applied to the entire body surface and that appropriate tests should be

chosen to reflect the intended use of the antimicrobial drug product

(39 FR 33103 at 33135), the manufacturer contended that the guidelines

were developed to address the most extreme exposure to an antimicrobial

ingredient rather than to describe the minimal requirements for safety

data that the Panel would find acceptable. Noting the contrast between

the use of surgical hand scrub drug products (products used by adults

in a limited area of the body for a specified time span) with lifetime

application to the entire body in bar soaps, the manufacturer contended

that while the use of a surgical hand scrub is considered chronic use,

the exposure to the antimicrobial ingredient during such use is limited

to the hand and half the distance to the elbow. The manufacturer

further suggested that one might simply regard the use of health-care

antiseptic ingredients in handwashes and surgical scrubs as repeated

daily use in a limited area of the body.

The manufacturer contended that data from a 2-year feeding study

would not contribute any information on the long-term safety of

chloroxylenol that is not already available from subchronic studies

(Ref. 35). In support of its contention, the manufacturer submitted

data from subchronic animal toxicity and human bathing studies (Ref.

18) previously submitted in response to the tentative final monograph

for OTC topical antimicrobial drug products and to the Antimicrobial II

Panel. The data also included computer simulation models (Ref. 36) of

plasma levels of chloroxylenol that might occur after dermal

applications of varying concentrations of the ingredient. The

simulations, based on urinary excretion data from human bathing

studies, predict a lack of potential for accumulation of the ingredient

in humans. Subsequent submissions from the same manufacturer included a

review article on the toxicity of chloroxylenol (Ref. 19), a

retrospective analysis of the value of chronic animal toxicology

studies of pharmaceutical compounds (Ref. 20), and copies of all

available toxicity data for chloroxylenol (Ref. 21). Included in the

toxicity data was a kinetic analysis (Ref. 37) of data from human and

animal studies of the ingredient previously submitted to the agency

that also predicts that accumulation in humans is not likely to occur

at reasonable exposure levels. Based on the above data and information,

the manufacturer requested that the agency reconsider the necessity of

a long-term animal study. In response to the manufacturer's request, a

public meeting was held to discuss the available toxicity data for

chloroxylenol. At that meeting, the agency noted that many of the

subchronic studies of the ingredient are of limited usefulness because

they were conducted using a formulated product that contained isopropyl

alcohol, turpineols, and castor oil soap in addition to chloroxylenol.

The kinetic model used in the studies was considered inappropriate. A

one-compartment model, as used in the analysis, is not relevant to

chloroxylenol due to its lipophilic nature. The agency's detailed

comments are on file in the Dockets Management Branch (Refs. 38 and

39).

After considering the manufacturer's comments and evaluating the

data available at the time, the agency concluded that the information

was not adequate to characterize the level of absorption, the

distribution, the metabolism, and the excretion of chloroxylenol

following topical administration. In a 1988 letter to the manufacturer

(Ref. 40), the agency stated: (1) That data from the human bathing

studies reviewed are highly variable (absorption 0.5 to 15.7 percent),

(2) the analytical methodology used in the studies had not been

validated and (3) that the small number of subjects included in the

studies made it difficult to draw meaningful conclusions from the

reported results. The agency commented further that submitted

accumulation predictions were not adequate to define the toxicity that

might occur with repeated exposure to the ingredient because no data

have been submitted to support or validate the model's assumptions in

characterizing exposure and stated that additional data are needed to

justify, support, and verify the assumptions and data used in the

predictions. Pointing out that accumulation is not the sole issue of

long-term toxicity, the agency asserted that long-term toxicity may be

related to repeated daily exposure to low levels of the ingredient over

a lifetime.

In that same letter, the agency stated that it had reexamined the

necessity for a long-term animal study based on the manufacturer's

assertion that use of the ingredient as an antiseptic handwash and

surgical scrub should be regarded as repeated use to a limited area of

the body, and had concluded that data from additional short-term

studies conducted under actual use conditions (i.e., where abrasion is

followed by occlusion, with the level of absorption, distribution,

metabolism, and elimination of the ingredient being shown under these

conditions) could provide adequate information to determine whether or

not a long-term animal study is necessary. Protocols for a

pharmacokinetic surgical scrub study to develop such data were

submitted to the agency (Refs. 41 and 42); however, to date the agency

has not received any data from such a study. The agency's detailed

comments are on file in the Dockets Management Branch (Refs. 43 and

44).

More recently, the agency received additional data pertaining to

the safety of chloroxylenol from another manufacturer (Ref. 30). The

data included an assessment of the ingredient's mutagenic potential by

a series of in vitro and in vivo assays (Ames test, unscheduled DNA

synthesis in rat primary hepatocytes, chromosomal aberrations in

Chinese hamster ovary cells, and an in vivo mouse micronucleus assay).

The data also included a dose range-finding study for a teratology

study of the ingredient in rats and the subsequent teratology study.

Two of the four mutagenicity assays included in the submission

yielded suspect or equivocal results. The in vitro administration of

19, 38, 75, and 150 micrograms per milliliter (g/mL) doses of

chloroxylenol to Chinese hamster ovary cells produced a statistically

significant increase relative to the solvent control in the mean number

of chromosome aberrations per cell at the 75 and 150 g/mL dose

level both in the presence and absence of metabolic activation.

Statistically significant increases in the percent of aberrant cells

were also seen at the 75 g/mL dose in the absence of metabolic

activation and at the 75 and 150 g/mL doses in the presence of

metabolic activation. No dose response was apparent in either the

activated or nonactivated systems. The investigator concluded that the

results were equivocal in the nonactivated test system and suspect in

the activated test system.

The results of the in vivo mouse micronucleus assay demonstrated a

statistically significant increase in micronucleated polychromatic

erythrocytes in female mice 24 and 72 hours after oral dosing with 250

and 833 milligrams per kilogram (mg/kg) doses of chloroxylenol.

However, no dose response was apparent. The investigator considered the

results to be a statistical anomaly based on unusually low mean

micronucleus values in the negative control group and the lack of a

dose response. However, the agency believes that because the observed

increases were significantly elevated over those of the negative

controls (p 0.01) and were reproducible at two dose levels,

these results should be considered equivocal. The manufacturer has

provided additional information (Ref. 45) in response to the agency's

interpretation of the results of the mouse micronucleus assay. However,

the agency continues to believe that reliance on data from historical

controls is inappropriate and has not changed its position on the data.

The agency's detailed comments are on file in the Dockets Management

Branch (Refs. 46 and 47).

In light of the new data (Ref. 30) and the issues that they raise,

the agency has again reexamined the data requirements necessary to

support the safe chronic use of this ingredient. The agency finds it

necessary to broaden the additional testing requirements in order to

clearly assess potential risks associated with chronic use of

chloroxylenol. Therefore, data obtained from the following are

necessary: (1) Human studies conducted under maximal use conditions,

i.e., repeated use as a surgical scrub use where abrasion is followed

by occlusion, characterizing the level of absorption, the distribution,

metabolism, and elimination of the ingredient, (2) a lifetime dermal

carcinogenicity study (up to 2 years) in mice, and (3) an appropriate

human epidemiological study performed to determine the effects on

health-care professionals in countries, such as England, where the

ingredient has been used extensively for a long period of time are

necessary. Further, in order to relate the data derived from the

chronic animal study to humans, the lifetime dermal carcinogenicity

study should also include concomitant absorption, distribution,

metabolism, and excretion studies. A protocol for an 18-month dermal

carcinogenicity study has been submitted to the agency (Ref. 48). The

agency's detailed comments and evaluation of the data and protocol are

on file in the Dockets Management Branch (Ref. 47).

Regarding the effectiveness of chloroxylenol, the agency stated the

following in the previous tentative final monograph: ``Claims for broad

spectrum activity have been made * * *; however, the Commissioner finds

that inadequate effectiveness data were submitted. Many studies were

old and not performed with modern antiseptic testing procedures. * * *

effectiveness testing both in vitro and in vivo should be done in

accordance with the Guidelines'' (43 FR 1238).

The applicable effectiveness data submitted by the comments were

derived from in vivo and in vitro studies (Refs. 1 through 7 and 13

through 16), along with data subsequently submitted under the

``feedback'' procedures (Refs. 22 through 28 and 50).

Data from in vivo glove juice studies (Refs. 1, 2, 19, and 50)

demonstrated the antiseptic activity of chloroxylenol in a range of 3

to 3.75 percent when formulated in an aqueous surfactant vehicle.

Chloroxylenol formulations are substantive in their activity, i.e.,

they do not produce an initial high reduction in the number of bacteria

but after repeated use (routine use), they reduce the baseline number

of bacteria and suppress bacterial growth for 6 hours. In vivo data for

surgical hand scrub products containing chloroxylenol at concentrations

lower than 3 percent are insufficient. Aqueous solutions of

chloroxylenol in a pine oil vehicle (1:40 dilution of Dettol)

consistently reduced more than 99 percent Staphylococcus aureus (S.

aureus) from the hands of test subjects (Ref. 25).

In vivo cup scrubbing and other appropriate data (Refs. 22, 23, and

24) indicate that chloroxylenol, in 70 percent alcohol, is fast acting

as a patient preoperative skin preparation. However, alcohol itself

meets the criteria for a preoperative skin preparation and is a

significant contributor for fast acting contaminant reduction. The data

are not sufficient to demonstrate that chloroxylenol in this

formulation contributes to the total antimicrobial effect.

In vitro study data (Refs. 1, 3, 4, 5, 13, 14, 16, and 26) show

that chloroxylenol in various vehicles is effective against gram-

negative bacteria, i.e., Escherichia coli (E. coli), P. aeruginosa,

Proteus vulgaris, and Klebsiella aerogenes (K. aerogenes). This anti-

gram-negative activity is formulation dependent. Tested aqueous

solutions of pure chloroxylenol with no other additives show that low

concentrations (0.3 mg/mL) reduced 95 percent of some Pseudomonas in 10

minutes.

Data regarding the antiseptic activity of chloroxylenol itself are

not adequate. While the data are considered sufficient to support in

vitro effectiveness for the finished products, the available data are

inadequate to show the contribution of the chloroxylenol. Because these

finished products contain several additional ingredients, e.g.,

surfactants, isopropanol, pine oil, or ethylenediaminetetraacetic acid

(EDTA), which contributed substantial germicidal activity, conclusions

regarding chloroxylenol's active contribution to the product's efficacy

cannot be supported. The agency's detailed comments and evaluations of

the submitted data are on file in the Dockets Management Branch (Refs.

51 and 52). One manufacturer has responded to FDA's concern and

provided additional data (Ref. 53). These data are currently being

reviewed by the agency and will be discussed in the final rule for

these drug products. In summary, the data are sufficient to support the

in vitro and in vivo effectiveness of the formulations tested. However,

additional data are needed to demonstrate that chloroxylenol

contributes to the activity of these formulations. In addition, data

from glove juice studies indicate that the antimicrobial activity of

chloroxylenol is substantive in nature and does not produce an initial

high reduction of bacteria, but that repeated use of the ingredient

will produce a reduction in bacteria as well as a suppression of the

baseline number of bacteria of the normal skin flora for 6 hours. As

discussed in section I.N., comment 28, the agency is proposing that all

antimicrobial products indicated for use as a surgical scrub or health-

care personnel handwash be able to demonstrate an immediate reduction

in bacteria and is inviting comment on the use of substantive

antimicrobials in health-care antiseptic drug products.

The agency, therefore, is proposing that chloroxylenol at the

concentrations evaluated (0.24 percent to 3.75 percent) be classified

as Category I for safety and Category III for effectiveness for short-

term use as a patient preoperative skin preparation and in Category III

for safety and effectiveness for long-term uses, i.e., antiseptic

handwash or health-care personnel handwash and surgical hand scrub. The

existing data are not adequate to extrapolate and assess the chronic

toxicity of chloroxylenol for long-term use. Before chloroxylenol may

be generally recognized as effective, the agency recommends that

appropriate in vitro and in vivo effectiveness data be submitted. The

data should include results obtained from both in vitro and in vivo

tests as described in the testing procedures below. (See section I.N.,

comment 28.)

References

(1) Unpublished Clinical Safety and Effectiveness Studies on

Aqueous Soap Formulations, Comment No. 0B7, Docket No. 75N-0183,

Dockets Management Branch.

(a) Controlled Clinical Study Comparing the Activity of Fresh,

Camay Soap, and Phisohex Against the Natural Bacterial Flora of the

Hand.

(b) Antimicrobial Activity of PCMX, Triclosan, and TCC.

(c) Repeated Insult Patch Testing of Fresh Soap.

(2) Unpublished Nonclinical and Clinical Studies, and Protocols,

Comment No. C96, Docket No. 75N-0183, Dockets Management Branch.

(a) Part I: PCMX Toxicosis, final reports of completed studies,

interim reports of incomplete studies, and Preclinical Testing

Protocol.

(b) Part II: Complete Reports on Clinical Safety and Efficacy

and In Vitro Efficacy Studies.

(3) Unpublished Clinical Effectiveness Studies on Aqueous Soap

Formulations, Comment No. C122, Docket No. 75N-0183, Dockets

Management Branch.

(a) Protocol and Results of a Glove Juice Hand Washing Test

Performed with PHLO Antimicrobial Skin Cleanser.

(b) Results of a Zone of Inhibition and Assay Performed on Aged

Samples of PHLO Antimicrobial Skin Cleanser.

(4) Unpublished Clinical Safety and Effectiveness Studies on

Aqueous Soap Formulations, Comment No. C123, Docket No. 75N-0183,

Dockets Management Branch.

(a) Bactericidal Activity of Envair Antiseptic Hand Soap.

(b) Dermal Irritation Study.

(c) Insult Patch Test.

(d) Bacterial Kill Test.

(e) Hand-wash Effectiveness Test.

(5) Unpublished In Vitro Effectiveness Studies Performed on

Aqueous Soap Solutions, Comment No. C125, Docket No. 75N-0183,

Dockets Management Branch.

(a) AOAC Available Chlorine Germicidal Equivalent Concentration

Test.

(b) The Antimicrobial Activity of a Sample.

(6) Published and Unpublished Nonclinical and Clinical Safety

Studies, Comment No. SUP11, Docket No. 75N-0183, Dockets Management

Branch.

(7) Comment No. SUP12, Docket No. 75N-0183, Dockets Management

Branch.

(8) Unpublished Clinical Safety an Effectiveness Studies,

Comment No. SUP10, Docket No. 75N-0183, Dockets Management Branch.

(a) The Effects of Vaseline Petroleum Jelly and Vaseline First

Aid Carbolated Petroleum Jelly on Epidermal Wound Healing--A

Controlled Clinical Laboratory Study, April 29, 1976.

(b) The Effect of Vaseline Petroleum Jelly and Vaseline First

Aid Carbolated Petroleum Jelly on Healing of Experimental Skin

Wounds, January 13, 1977.

(9) Bradbury, S. J., and J. Hayden, ``Effect of DettolR

Wound Healing in Rats,'' Report No. RC 76132, unpublished study,

Comment No. SUP5, Docket No. 75N-0183, Dockets Management Branch.

(10) Bradbury, S.J., and E.J. Hayden, ``DettolR Wound

Healing,'' unpublished study, Project No. RC 1081, 1978, Comment No.

SUP12, Docket No. 75N-0183, Dockets Management Branch.

(11) Maibach, H.I., ``The Effects of VaselineR Petroleum

Jelly and VaselineR First Aid Carbolated Petroleum Jelly on

Epidermal Wound Healing--A Controlled Clinical Laboratory Study,''

unpublished study, Comment No. SUP10, Docket No. 75N-0183, Dockets

Management Branch.

(12) Maibach, H.I., ``The Effect of VaselineR Petroleum

Jelly and VaselineR First Aid Carbolated Petroleum Jelly on

Healing of Experimental Skin Wounds,'' unpublished study, Comment

No. SUP10, Docket No. 75N-0183, Dockets Management Branch.

(13) Munton, T.J., and J. Prince, ``The Bacteriostatic and

Bactericidal Activity of DettolR Against a Range of Recently

Isolated Mesophilic Strains Including Members of the Normal Flora

and Cutaneous Pathogens of the Skin,'' unpublished study, No. BL 75/

4, 1975, Comment No. SUP3, Docket No. 75N-0183, Dockets Management

Branch.

(14) Prince, J., and K.A. Barker, ``A Comparison of the In-Vitro

Activity of DettolR, Hexylresorcinol, and Benzalkonium

Chloride,'' unpublished study, No. BL 76/28, 1976, Comment No. SUP3,

Docket No. 75N-0183, Dockets Management Branch.

(15) Munton, T.J., and J. Prince, ``The Bactericidal Activity of

DettolR on Skin Artificially Contaminated with Micro-organisms

Using the Replica Plating Technique,'' unpublished study, No. BL 75/

14, RC 7565, 1975, Comment No. SUP3, Docket No. 75N-0183, Dockets

Management Branch.

(16) ``Scientific Information on the `In-vitro' and `In-vivo'

Antimicrobial Activity of DettolR as Determined in the

Bacteriological Laboratories of Reckitt and Colman, Hull,''

unpublished report, Comment No. C62, Docket No. 75N-0183, Dockets

Management Branch.

(17) Comment No. LET65, Docket No. 75N-0183, Dockets Management

Branch.

(18) Comment No. SUP47, Docket No. 75N-0183, Dockets Management

Branch.

(19) Guess, W.L., and M.K. Bruch, ``A Review of Available

Toxicity Data on the Topical Antimicrobial Chloroxylenol,'' Journal

of Toxicology Cutaneous and Ocular Toxicology, 5:233-262, 1986.

(20) Lumley, C.E., and S.R. Walker, ``The Value of Chronic

Animal Toxicology Studies of Pharmaceutical Compounds: A

Retrospective Analysis,'' Fundamental and Applied Toxicology,

5:1007-1024, 1985.

(21) Comment No. RPT6, Docket No. 75N-0183, Dockets Management

Branch.

(22) Davies, J. et al., ``Disinfection of the Skin of the

Abdomen,'' British Journal of Surgery, 65:855-858, 1978.

(23) Frazer, J., ``The Effect of Two Alcohol Based Antiseptics

on Artificially Contaminated Skin,'' Microbios Letters, 3: (10) 119-

122, 1976.

(24) Byatt, M.E., and A. Henderson, ``Preoperative Sterilization

of the Perineum: A Comparison of Six Antiseptics,'' Journal of

Clinical Pathology, 26:921-924, 1973.

(25) Lowbury, E.J.L., H.A. Lilly, and J. P. Bull, ``Disinfection

of Hands: Removal of Transient Organisms,'' British Medical Journal,

2:230-233, 1964.

(26) Caplin, H., and D.C. Chapman, ``A Comparison of Three

Commercially Available Antiseptics Against Opportunist Gram-Negative

Pathogens,'' Microbios, 16:133-138, 1976.

(27) Comment No. SUP48, Docket No. 75N-0183, Dockets Management

Branch.

(28) Comment No. RPT3, Docket No. 75N-0183, Dockets Management

Branch.

(29) Comment No. RC6, Docket No. 75N-0183, Dockets Management

Branch.

(30) Comment No. C171, Docket No. 75N-0183, Dockets Management

Branch.

(31) Letter from W.E. Gilbertson, FDA, to C. Rose, Pennwalt

Corp., coded LET54, Docket No. 75N-0183, Dockets Management Branch.

(32) Letter from C. Rose, Pennwalt Corporation, to W.E.

Gilbertson, FDA, coded LET59, Docket No. 75N-0183, Dockets

Management Branch.

(33) Letters from W.E. Gilbertson, FDA, to J. Nalls, Ferro

Corp., C. Rose, Pennwalt Corp., M.E. Garabedian, Dexide, Inc., M.

Berdick, Chesebrough-Ponds, Inc., W.F. Stephen, Scientific and

Regulatory Services, H.S. Chapman, Chemical Specialties, Inc., C.A.

Wiseman, Sani-Fresh, Division of Envair, Inc., J. Rowan, Seagull

Chemical, Inc., coded LET70, LET71, LET72, LET73, LET74, LET75,

LET76, and LET77, respectively, in Docket No. 75N-0183, Dockets

Management Branch.

(34) Comment No. LET65, volumes 1 through 3, Docket No. 75N-

0183, Dockets Management Branch.

(35) Memorandum of meeting between representatives of Dexide,

Inc., Ferro Corp., and FDA, coded MM8, Docket No. 75N-0183, Dockets

Management Branch.

(36) Stavchansky, ``Computer Simulations of Chloroxylenol,''

unpublished report, Comment No. SUP47, Docket No. 75N-0183, Dockets

Management Branch.

(37) Cabana, B.E., and E.D. Purich,''Comparative Metabolism and

Pharmacokinetics of Chloroxylenol (PCMX) in Animals and Man,''

unpublished report, Comment No. RPT6, Volume 7, Docket No. 75N-0183,

Dockets Management Branch.

(38) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,

Inc., coded LET79, Docket No. 75N-0183, Dockets Management Branch.

(39) Memorandum of meeting between representatives of Dexide,

Inc., Ferro Corp., and FDA, coded MM11, Docket No. 75N-0183, Dockets

Management Branch.

(40) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,

Inc., coded LET89, Docket No. 75N-0183, Dockets Management Branch.

(41) Comment No. C165, Docket No. 75N-0183, Dockets Management

Branch.

(42) Comment No. SUP51, Docket No. 75N-0183, Dockets Management

Branch.

(43) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,

Inc., coded LET93, Docket No. 75N-0183, Dockets Management Branch.

(44) Memorandum of meeting between representatives of Dexide,

Inc., Ferro Corp., and FDA, coded MM15, Docket No. 75N-0183, Dockets

Management Branch.

(45) Comment No. C172, Docket No. 75N-0183, Dockets Management

Branch.

(46) Letter from W. E. Gilbertson, FDA, to G. R. Kramzar, NIPA

Laboratories, Inc., coded LET97, Docket No. 75N-0183, Dockets

Management Branch.

(47) Letter from W. E. Gilbertson, FDA to G. R. Kramzar, NIPA

Laboratories, Inc., coded C174, Docket No. 75N-0183, Dockets

Management Branch.

(48) Comment No. C173, Docket No. 75N- 0183, Dockets Management

Branch.

(49) Comment No. LET65, vol. 4, 5, and 6, Docket No. 75N-0183,

Dockets Management Branch.

(50) McCracken, A., ``Effectiveness of Ultradex Scrub Sponge

Determined in a Clinical Setting,'' unpublished study, coded LET65,

vol. 6, Docket No. 75N-0183, Dockets Management Branch.

(51) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,

Inc., coded LET87, Docket No. 75N-0183, Dockets Management Branch.

(52) Letter from W. E. Gilbertson, FDA, to M. K. Bruch, Dexide,

Inc., coded LET90, Docket No. 75N-0183, Dockets Management Branch.

(53) Letter from M. K. Bruch, Dexide, Inc., to W. E. Gilbertson,

FDA, coded LET91, Docket No. 75N-0183, Dockets Management Branch.

H. Comment on Hexachlorophene

13. One comment urged reconsideration of hexachlorophene as an OTC

``handwashing agent and antimicrobial skin cleanser for use in the

hospital, doctor's office, and by adult consumers.'' The comment stated

that adequate data to support Category I status were submitted in

response to the advance notice of proposed rulemaking, but were only

superficially discussed by the agency in comment 61 of the tentative

final monograph. (See the Federal Register of January 6, 1978, 43 FR

1210 at 1220.) The comment submitted additional data to support the

safety of hexachlorophene, including a retrospective study on 3 percent

hexachlorophene in baby bathing (Ref. 1) and a study of hexachlorophene

blood levels in infants receiving routine antiseptic skin care (Ref.

2). The comment also included a comprehensive review article on the

safety and effectiveness of hexachlorophene (Ref. 3).

The agency has reevaluated the data discussed in comment 61 in the

tentative final monograph (43 FR 1220) and evaluated the new data, and

has determined that the data do not warrant changing the classification

of hexachlorophene as a prescription drug. The infant data (Refs. 1 and

2) were discussed in detail in the tentative final monograph for OTC

antimicrobial diaper rash drug products (55 FR 25246 at 25261 to

25263).

Summaries of handwash studies were also submitted, but no data were

included. In one study, 3 percent hexachlorophene was tested as a

surgical scrub under exaggerated use conditions (Ref. 4). Subjects

(number not specified) washed their hands and forearms in 20 mL

hexachlorophene for 10 minutes, 5 times daily, 6 days a week for a

total of 58 days. No signs of toxicity were reported. The blood levels

of hexachlorophene reached a plateau within 3 days at mean levels of

0.07 g/mL.

The agency believes that it would be necessary to test a very large

group of subjects (the number of subjects required to obtain a

statistically significant result) with a variety of skin conditions to

determine the true degree of absorption. A similar study reviewed by

the Panel (39 FR 33103 at 33118) reported blood levels of 0.5

g/mL or higher.

In the other study, subjects washed their hands and face three

times daily for 3 weeks with either 2 or 5 mL of 3 percent

hexachlorophene (Ref. 4). Blood concentrations reached a plateau within

7 days at mean levels of 0.21 g/mL for the 2-mL group and 0.22

g/mL for the 5-mL group.

Other additional data contained only a brief summary of the

historical use of hexachlorophene and primarily cited publications in

the medical literature (Ref. 5). The references provided no new

information. Consequently, the agency has determined that

hexachlorophene will continue on prescription status subject to the

existing regulation in 21 CFR 250.250.

In order for hexachlorophene to be switched to OTC status, the

concerns expressed by the Antimicrobial I Panel that hexachlorophene

does not have an adequate margin of safety for OTC use (39 FR 33103 at

33117) should be addressed. After reviewing the submitted data, the

agency concludes that the safety of this ingredient for OTC use on

infants has not been demonstrated. For OTC status for use by adults,

any further submission of data should specifically address the safe OTC

use of hexachlorophene in adults.

Based upon the discussion above, the agency is proposing that

hexachlorophene remain available by prescription only, except when used

as a preservative at concentrations of 0.1 percent or less.

The agency's detailed comments and evaluation of the data are on

file in the Dockets Management Branch (Ref. 6).

References

(1) Plueckhahn, V. D., and R. B. Collins, ``Hexachlorophene

Emulsions and Antiseptic Skin Care of Newborn Infants,'' Medical

Journal of Australia, 1:815-819, 1976.

(2) Plueckhahn, V. D., ``Blood Hexachlorophene Concentrations in

New-Born Infants Undergoing Routine Antiseptic Skin Care with a 3%

Hexachlorophene Emulsion,'' unpublished study contained in SUP13,

Docket No. 75N-0183, Dockets Management Branch.

(3) Plueckhahn, V. D., ``Infant Antiseptic Skin Care with

Hexachlorophene Emulsions and Powders,'' unpublished study contained

in SUP28, Docket No. 75N-0183, Dockets Management Branch.

(4) Comment No. SUP13, Docket No. 75N-0183, Dockets Management

Branch.

(5) Comment No. C116, Docket No. 75N-0183, Dockets Management

Branch.

(6) Letter from W. E. Gilbertson, FDA, to G. S. Goldstein,

Sterling Drug Inc., coded LET63, Docket No. 75N-0183, Dockets

Management Branch.

I. Comments on Iodine and Iodophors

14. One comment pointed out that poloxamer-iodine complex appeared

to be incorrectly included in the Category II list under ``health-care

personnel handwash'' (43 FR 1210 at 1227), while it is properly listed

in Category III for use as a ``health-care personnel handwash'' (43 FR

1210 at 1229). The comment stated that deletion from the Category II

list would correct the error.

The agency concurs with the comment that poloxamer-iodine complex

for use as a health-care personnel handwash was incorrectly listed as

Category II (43 FR 1227) and that the listing as Category III (43 FR

1229) was correct.

15. One comment submitted data on the safety and effectiveness of a

``mixed iodophor'' consisting of iodine complexed by ammonium ether

sulfate and polyoxyethylene sorbitan monolaurate (Ref. 1). The comment

stated that this information had been previously submitted in May 1974,

but that the ingredient had not been mentioned in the Panel's report or

in the agency's proposed monograph and requested that the agency

include it in the monograph. The comment pointed out that the iodophor,

formulated as a liquid hand scrub, is intended for use by surgeons,

food handlers, and others for whom reduced bacterial skin flora is of

public health significance.

Regarding the comment's statement that the data were previously

submitted, the agency has no record of any submission of these data in

1974. Because this hand scrub was not previously reviewed or

categorized as an OTC topical antimicrobial drug product, the agency

reviewed the product's marketing history and considers it appropriate

to include this product in the OTC drug review. The agency has

evaluated the data submitted by the comment (Ref. 1) and determined

that iodine complexed by ammonium ether sulfate and polyoxyethylene

sorbitan monolaurate is safe for use as a surgical hand scrub and

health-care personnel handwash, but that there are insufficient data

available to determine its effectiveness for these uses. Therefore, the

ingredient is being classified in Category III.

The data included several studies on the absorption of the iodine

complex, blood levels of iodine, and the systemic toxicity of the

iodine complex. Protein-bound iodine (PBI) and iodine blood levels in

rabbits were determined following two studies of acute dermal

applications. In the first study, either 2 or 5 mL/kilogram (kg) of the

test iodine complex was applied to the shaved backs of rabbits in one

experiment. The method of occlusion, if any, was not stated, but the

test material was washed off after 24 hours. In another experiment, 2

mL/kg of the test iodine complex was compared with a povidone-iodine

complex and both were applied as in the first experiment. PBI and total

iodine in blood were determined at 0, 24, and 48 hours in both

experiments. In all treated animals, the level of PBI was extremely

high at certain times, primarily at 24 hours. Animals receiving the

higher dose of iodine complex in the first experiment seemed to return

to normal sooner than those receiving the lower dose. All animals

returned to normal by 14 days. For purposes of comparison, the second

experiment showed that serum total iodine increased from 1.4 to 30.7

milligrams/deciliter (mg/dL) in the test iodine complex group compared

to from 1.23 to 37.9 mg/dL in the povidone-iodine group in the 24 hours

that the application remained on. In the second study, 5 mL/kg of the

test iodine complex was applied to the shaved backs of two groups of

five rabbits each. In one group the shaved backs were occluded for 24

hours and in the other group, the shaved backs were scrubbed for 10

minutes followed by rinsing and occlusion. An additional group served

as an untreated control group. Blood samples for iodine determinations

were taken at 0, 24, and 48 hours and at 14 days. All five animals in

the group in which the iodine complex remained occluded on intact skin

for 24 hours had markedly elevated levels of PBI and iodine at both 24

and 48 hours, but were only slightly above normal at 14 days. For the

10-minute scrub animals, the PBI levels were increased in two of five

animals at 24 hours, slightly in all five animals at 48 hours, and were

normal at 14 days.

A study to determine the effect on blood PBI levels of a routine

scrubbing procedure in which exposure to the iodine complex exceeded

normal use showed no alteration in PBI levels in four humans who

scrubbed twice daily (each scrub consisting of two 5 minute hand washes

with 5 mL) for 26 consecutive days. Also, no irritation was observed.

In a similar study in which the subjects wore gloves for 2 hours after

each scrub, PBI levels were not increased, but total iodine was

slightly increased. In two subjects, this increase was greater in the

middle of the study, but the total iodine blood levels were near normal

by the end of the study.

A dermal absorption study in which the shaved backs of four monkeys

were rubbed with 0.17 mL/kg of radioactive iodine complex for 10

minutes, rinsed, wrapped for 2 hours, and the animals sacrificed after

24 hours, revealed that less than 0.1 percent of the application was

recovered in the thyroid, the target organ for iodine.

A 90-day sub-acute dermal toxicity study was conducted in three

groups of monkeys divided into one control group and two test groups.

One test group was scrubbed once for 10 minutes daily with 0.17 mL/kg

of the iodine surgical scrub detergent product and the second group was

scrubbed three times with 0.34 mL/kg (once for 10 minutes and twice for

3 minutes each day). To simulate the wearing of surgical gloves, the

treated area of each animal, which consisted of a shaved area of the

back equivalent to about 10 percent of the body area, was wrapped with

a rubber dam for 30 to 90 minutes. The study lasted 13 weeks during

which the animals were monitored. Neither test group showed any effects

of iodophor treatment except elevated PBI levels in the high dose

group, which peaked at one month. Also, there was no significant effect

on the thyroid in the treated groups.

The agency believes this iodine complex is safe for humans based on

the data from human, rabbit, and monkey studies. Test data showed very

little iodine absorption when the product was used as a scrub,

negligible uptake (following acute dermal application of radioactive

iodine complex) by the thyroid in monkeys, and an unchanged thyroid

weight in test groups of monkeys following 90 days of sub-acute

applications of the iodine complex.

The comment submitted data from one clinical study for evaluating

effectiveness as a surgical hand scrub but did not provide the testing

protocol used. Five subjects scrubbed three times daily for 5 days with

the iodophor formulation (containing 1.1 percent iodine). Four subjects

completed the study. Surgical gloves were worn for 2 hours after the

first wash of the day. Subjects' hands were sampled once each day at

the end of the 2-hour gloved period using a single-basin Cade method.

The initial sampling was used to establish a baseline microbial count

for each subject. Study results were reported as the number of

organisms per mL of basin water and the percent reduction in the number

of organisms recovered. The reduction in the bacterial population

ranged from 89 to 98 percent on the first day. By the fifth day, the

reduction ranged from 99 to 100 percent. Similar results were obtained

in a comparative study on six subjects using povidone-iodine.

Although it is clear that the test used was not the glove juice

test which is described in the antimicrobial tentative final monograph

(43 FR 1210 at 1242), alternative methods may be acceptable. However,

because of the small number of subjects included in the study, the data

are not sufficient to support the Category I classification of this

ingredient for use as a surgical hand scrub. Additional studies, of the

type described in Sec. 333.470(b)(1) of this amended tentative final

monograph, are necessary to support the effectiveness of this

surfactant iodine complex for this use.

In the previous tentative final monograph (43 FR 1235), the agency

recognized that elemental iodine complexed with a surfactant type

``carrier'' molecule reduces the amount of immediate ``free'' iodine,

because most of the formulated iodine is bound in the complex.

Effectiveness of all iodophors is dependent on the release of free

iodine as the active agent from the complexing molecule which acts only

as a carrier. The agency acknowledges that iodine complexed with a

surfactant is an acceptable way of presenting iodine as an

antimicrobial agent to the skin. However, because most of the

formulated iodine may be tied up in the complex and because the

information submitted by the comment to support in vitro efficacy (Ref.

2) dealt only with aqueous and/or tincture solutions of free iodine,

testing of the complete formulation is necessary to judge the

importance of formulation on the release of the active ingredient and,

thus, its influence on aspects of effectiveness.

Based on the data submitted, the agency concludes that iodine

complexed by ammonium ether sulfate and polyoxyethylene sorbitan

monolaurate is safe but additional data from appropriate studies are

needed to establish general recognition of effectiveness for use as a

surgical hand scrub and health-care personnel handwash. The data should

include results obtained from both in vitro and in vivo testing

procedures. (See section I.N., comment 28.)

References

(1) Unpublished Nonclinical and Clinical Studies on V.I.S.,

Vestal Iodine Scrub (iodine complexed by ammonium ether sulfate and

polyoxyethylene sorbitan monolaurate), Comment No. C106, Docket No.

75N-0183, Dockets Management Branch.

(a) Acute Dermal Toxicity in Rabbits.

(b) Acute Dermal Application--Rabbits.

(c) Determination of the Influence of Scrubbing with Vestal

Iodine Surgical Scrub Detergent on the Protein Bound Iodine Level of

the Blood.

(d) Determination of the Influence of Scrubbing with Vestal

Iodine Surgical Scrub Detergent on the Protein Bound Iodine and

Total Serum Iodine Levels in the Blood.

(e) Percutaneous Absorption of Iodine in Monkeys from the Dermal

Application of an Iodine Surgical Scrub Detergent.

(f) Three Month Sub-Acute Dermal Toxicity Study in Monkeys with

Vestal Iodine Scrub Detergent.

(g) Iodine Surgical Scrub Detergent, Surgical Hand Scrub Study

in Five Human Test Subjects.

(2) Gershenfeld, L., ``Iodine,'' in ``Disinfection,

Sterilization, and Preservation'' 1st ed., Lee and Febiger,

Philadelphia, pp. 329-347, 1968.

16. Several comments objected to the warning proposed for the

professional labeling for povidone-iodine and iodophor-surfactant

products: ``Caution: Do not use this product in the presence of starch-

containing products. Starch can adsorb iodophors and the resulting

complex can cause serosal adhesions (abnormal union of the serous

membranes) and other undesirable effects in the body'' (43 FR 1210 at

1221). The comments pointed out that the study by Goodrich, Prine, and

Wilson (Ref. 1) on which the warning is based is not well controlled,

is rudimentary, and lacks rigorous testing that produces evidence which

can be statistically analyzed. The comments contended that this article

is not sufficient basis for the warning. The comments requested that

the impact of the article by Goodrich, Prine, and Wilson on the

labeling of nonsurfactant iodophors be reevaluated and that povidone-

iodine be exempt from the required warning relating to contact of

starch and iodophors. One comment stated that there are numerous papers

in the literature describing the antiadhesive effect of povidone and

povidone-iodine and submitted nine references dealing with humans and

animals that support an antiadhesive effect when povidone or povidone-

iodine is used in intraperitoneal surgery (Ref. 2). Another comment

explained that starch is well known for producing granuloma and that

every package of surgeons' gloves carries a warning statement to the

effect that the outside of the gloves must be cleansed of starch powder

prior to use. The comment concluded that FDA should require a warning

label on the gloves, but not on products containing the drug.

FDA has reevaluated the article by Goodrich et al. (Ref. 1),

considered the additional cited references (Ref. 2), and examined

current policy on the labeling of United States Pharmacopeia (U.S.P.)

Absorbable Dusting Powder (cornstarch). Goodrich, Prine, and Wilson

(Ref. 1) provide data from observations and arbitrary scoring of

adhesions after intraperitoneal injection into 4 groups of 13 adult

female mice with: (1) Powdered starch suspended in 1.5 mL of normal

saline, (2) powdered starch treated with 5 mL of an iodophor and washed

three times in saline before resuspension in 1.5 mL normal saline, (3)

powdered starch treated with 5 mL of a 10-percent solution of

surfactant washed three times in saline and resuspended in 1.5 mL of

normal saline and (4) normal saline (control animals). The data do not

indicate any significant difference between suspensions of the

surfactant mixed with starch and the surfactant-iodophor mixed with

starch. The agency's policy on the labeling of surgical gloves treated

with Absorbable Dusting Powder U.S.P., determined upon evidence

presented during the Drug Efficacy Study Implementation, was published

in the Federal Register of May 25, 1971 (36 FR 9475). The agency

requires the following statement on surgical gloves treated with

Absorbable Dusting Powder U.S.P.: ``Caution: after donning, remove

powder by wiping gloves thoroughly with a sterile wet sponge, sterile

wet towel, or other effective method.'' Products containing Absorbable

Dusting Powder U.S.P. for lubricating surgical gloves were formerly

classified as new drugs, but are now regarded as transitional devices,

for which premarket approval is required under the Medical Device

Amendments to the Federal Food, Drug, and Cosmetic Act (42 FR 63472 at

63474). FDA's Center for Devices and Radiological Health is

establishing categories for all surgical devices, including surgical

gloves lubricated with powdered starch. Any changes in the labeling for

this class of products will be dealt with in a separate rulemaking

procedure and separate Federal Register notice.

The agency believes that the user's removal of dusting powder from

surgical medical devices (rubber goods) treated with Absorbable Dusting

Powder U.S.P. decreases the incidence of adhesions and is not persuaded

that the data in the article by Goodrich, Prine, and Wilson provide a

sufficient scientific basis for a warning label. Therefore, the warning

about the interaction of iodophors and starch-containing products

proposed in comment 66 of the previous tentative final monograph is not

included in this amended tentative final monograph.

References

(1) Goodrich, E. O., J. R. Prine, and J. S. Wilson, ``Iodized

Starch Granules as a Cause of Starch Peritonitis,'' Surgical Forum,

25:372-374, 1974.

(2) Nonclinical and Clinical Safety Studies on Postoperative

Observations of Abrasions, Comment No. C111, vol. 4, tabs 6-14,

Docket No. 75N-0183, Dockets Management Branch.

17. A number of comments submitted new data (Ref. 1) to establish

that povidone-iodine is safe and effective as a topical antimicrobial

drug. The comments requested that povidone-iodine be reclassified from

Category III to Category I as a topical antimicrobial ingredient for

use as an antimicrobial soap, health-care personnel handwash, surgical

hand scrub, patient preoperative skin preparation, skin antiseptic,

skin wound cleanser, and skin wound protectant.

As discussed earlier in this document, this amended tentative final

monograph addresses only topical antiseptics for health-care antiseptic

uses as a surgical hand scrub, antiseptic handwash or health-care

personnel handwash, and patient preoperative skin preparation. As

discussed in section I.B., comment 5, antimicrobial soaps are no longer

included in this rulemaking. The agency addressed the other use

categories mentioned in the comment in a separate Federal Register

notice for OTC first aid antiseptic drug products (56 FR 33644). As

discussed in comment 38 of that document (56 FR 33660), FDA has

tentatively concluded that povidone-iodine should be classified in

Category I for use as a first aid antiseptic (formerly designated skin

antiseptic, skin wound cleanser, and skin wound protectant).

The agency has considered the new data submitted and other

information in support of the request to reclassify povidone-iodine

from Category III to Category I. On the basis of these data and

information, the agency tentatively concludes that povidone-iodine

should be reclassified from Category III to Category I as a topical

antiseptic ingredient for use in surgical hand scrub, patient

preoperative skin preparation, and health-care personnel or antiseptic

handwash drug products.

The general safety aspects of povidone-iodine that concerned the

agency in the previous tentative final monograph (43 FR 1210 at 1234 to

1236) are addressed elsewhere as follows: (1) The effect of povidone-

iodine on wound healing. Based upon submitted data, the agency

concluded in the first aid antiseptic segment of this rulemaking that

non-surfactant iodophor products (povidone-iodine) do not delay wound

healing. See comment 42 of that document (56 FR 33644 at 33662). Also,

the Advisory Review Panel on OTC Antimicrobial II Drug Products

reviewed povidone-iodine's effect on wound healing in its report on

topical antifungal drug products and concluded that the drug did not

affect wound healing (47 FR 12480 at 12545). (2) The effect of

povidone-iodine on thyroid function. In comment 41 of the tentative

final monograph for OTC first aid antiseptic drug products (56 FR 33644

at 33661), the agency discusses studies that indicate that topically

applied povidone-iodine does not cause thyroid dysfunction. (3) The

proposed warning about the interaction of starch-containing products

with iodophors resulting in serosal adhesions and other undesirable

effects, i.e., ``Caution: Do not use this product in the presence of

starch-containing products. Starch can adsorb iodophors and the

resulting complex can cause serosal adhesions (abnormal union of the

serous membranes) and other undesirable effects in the body'' (43 FR

1210 at 1221). The agency has reevaluated the proposal and decided that

the warning is not supported by the data. (See section I.I., comment

16.) (4) The agency's concern regarding molecular weights of povidone-

iodine greater than 35,000 daltons not being excreted by the kidney and

causing lymph node changes. In section I.I., comment 18, the agency

discusses a previously proposed warning regarding this subject and

determines, based on more recent data, that larger povidone-iodine

molecules are not a risk when the product is limited to the topical

uses included in this tentative final monograph.

The agency's concern about the need for expiration dates (not to

exceed 2 years after manufacture) because of the lack of stability data

for several iodophor preparations, which relates to the effectiveness

of the product, can be satisfied by compliance with the current good

manufacturing practices regulations (21 CFR parts 210 and 211). These

regulations include, among other things, requirements regarding

stability testing and expiration dating (see Secs. 211.137 and

211.166). Therefore, as discussed in comment 40 of the tentative final

monograph for OTC first aid antiseptic drug products (56 FR 33644 at

33661), data on the stability of povidone-iodine and the proposed 2-

year expiration date are no longer considered needed in this rulemaking

proceeding.

A second agency concern relating to effectiveness was the rate of

release of ``free'' iodine from the complex and whether there was

evidence of germicidal activity over a period of time in clinical

application (43 FR 1210 at 1235). As discussed in the tentative final

monograph for OTC topical acne drug products (comment 5, 50 FR 2172 at

2173), iodine is released from the povidone-iodine complex within

milliseconds, thus resolving this concern.

With regard to the effectiveness of health-care antiseptic uses

subject to this rulemaking, the agency has reviewed the data and

information on povidone-iodine's germicidal in vitro and antiseptic in

vivo effectiveness (Refs. 1 through 19) and concludes that the data are

sufficient to reclassify this ingredient from Category III to Category

I.

A series of in vitro controlled studies (Ref. 1-C133, Volume 1)

included a broad spectrum of test micro-organisms which were associated

with between 40 to 60 percent of the nosocomial infections in the

urinary tract, surgical wounds, pneumonia, and bloodstream, reported by

the National Nosocomial Infections Surveillance System (NNIS) for the

period from January 1985 to August 1988 (Ref. 2). In most instances,

these test micro-organisms, as proposed in Sec. 333.470(a)(1)(ii) (see

section I.C., comment 6), were killed after 0.5 to 5 minutes exposure

to povidone-iodine. A minimum inhibitory concentration (MIC) study

(Ref. 1-C133) using 30 cultures, both American Type Culture Collection

(ATCC) and recent skin isolates, was also included in this series of in

vitro studies. The results indicated a range for MIC from 87 parts per

million (ppm) to 492 ppm for dilutions of povidone-iodine solution and

83 ppm to 476 ppm for dilutions of povidone-iodine surgical scrub

depending on the test micro-organism. Tests with controls, neutralizer,

and organic load using a serial dilution method were included in the

study.

Gocke, Ponticas, and Pollack (Ref. 3) evaluated the susceptibility

of 230 clinical isolates from blood, urine, sputum, and wound cultures

to the bacteriocidal activity of povidone-iodine. These clinical

isolates contained over half the organisms included in

Sec. 333.470(a)(1)(ii). Results indicated that 106 of the 230 organisms

tested (46 percent) were killed when 1 mL of a standardized suspension

containing 10\8\ organisms was exposed to a 10 percent povidone-iodine

solution for 15 seconds. Povidone-iodine showed its highest activity

against gram-negative isolates, with 72 of the 94 isolates (75 percent)

being killed after a 15-second exposure. Only 34 of the 134 (25

percent) gram-positive isolates were killed under the same conditions.

However, further testing of organisms not killed after a 15-second

exposure indicated that increases in exposure time to 120 seconds

killed all of the previously ``resistant'' isolates. The study design

incorporated the use of a neutralizer and controls.

The effectiveness of a povidone-iodine formulation on micro-

organisms in a clinical setting was demonstrated by Michael (Ref. 4).

The study included 100 subjects with decubitus ulcers following a

spinal cord injury. Cultures of the wounds were taken prior to, during,

and upon completion of a once-a-day povidone-iodine treatment. Prior to

treatment, subjects had positive cultures for the following organisms:

S. aureus (60 subjects), Klebsiella/Enterobacter species (20 subjects),

E. coli (15 subjects), and Pseudomonas species (15 species). Following

an 8-to-10 week period of treatment with povidone-iodine, cultures

revealed that 90 of the 110 subjects no longer had positive cultures

for these organisms.

Pereira, Lee, and Wade (Ref. 5) conducted an in vivo gloved hand

test that is supportive of the effectiveness of povidone-iodine as a

surgical hand scrub. They examined the effects of surgical scrub

duration and type of antiseptic on the reduction of resident microbial

flora. Thirty-four subjects scrubbed with a 7.5 percent povidone-iodine

formulation or another antiseptic formulation using either a 5 minute

initial/3 minute consecutive scrub procedure or a 3 minute initial/30

second scrub procedure. Subjects were assigned to one of four groups,

and each group was assigned to one of the four treatments. Sampling was

done by the glove juice method using a sampling solution containing a

neutralizer. Glove juice samples were taken from both hands immediately

before scrubbing (baseline), from the nondominant hand immediately

after the initial scrub, 2 hours after the initial surgical scrub but

before the consecutive scrub (dominant hand), and 2 hours after one

consecutive surgical scrub (dominant hand). No significant difference

was found between the two durations of scrubbing with povidone-iodine.

Povidone-iodine produced an immediate 1.2 log10 reduction on the

dominant hand after an initial 5 minute scrub and a 1.0 log10

reduction on the dominant hand immediately after the 3 minute initial

scrub. Baseline was not exceeded 2 hours after either the 5 or 3 minute

scrub.

Aly and Maibach (Ref. 6) evaluated the characteristics of two

antimicrobial impregnated surgical hand scrub sponge/brush drug

products. The study, which included a widely used povidone-iodine

impregnated surgical hand scrub sponge/brush, evaluated both the

immediate and persistent effect on the resident bacterial flora of the

hands plus the effect of blood on the persistent antimicrobial activity

of the surgical hand scrub drug products. In the first phase of the

study, 13 subjects with left and right hand baseline counts of

>106 organisms were randomly assigned to perform a total of 11

scrubs with the povidone-iodine impregnated sponge/brush. Glove juice

samples were taken from the right hand of each subject immediately

following the first scrub of the day and from the left hand at either 3

or 6 hours. The entire procedure was repeated on test days 2 and 5. A

similar procedure was used in phase two of the study, except that 2 mL

of bacteriologically sterile blood was spread over the hands of 6

subjects following the initial scrub, and sampling occurred only at 3

and 6 hours. Neutralizers were incorporated into the stripping

solution, diluent, and culture media. On day 1, povidone-iodine

produced an immediate mean log10 reduction of 1.2, and baseline

was not exceeded at 3 hours. On days 2 and 5, povidone-iodine produced

immediate mean log10 reductions of 2.2 and 2.8, respectively, and

bacterial counts did not exceed baseline at 6 hours. While counts for

povidone-iodine approached baseline in the presence of blood, counts

did not exceed baseline at 6 hours on any day.

Another study (Ref. 1-C104), employing a method similar to the

effectiveness testing procedures described in proposed

Sec. 333.470(b)(2) of this amended tentative final monograph,

demonstrated the effectiveness of povidone-iodine 5 percent as a

health-care personnel handwash. Twenty-five consecutive handwashings

were done in 10 human subjects with a 5 minute rest between washings.

Before each washing the hands were dipped in broth culture containing

2.0 x 109 organisms (Bacillus subtilis var. niger ATCC 9372) per

mL; the contaminant was spread up over the wrists to the forearms.

Bacterial counts were done at the completion of every fifth washing by

the glove juice sampling method. Both the dilution fluid and growth

media incorporated a neutralizer. The transient microbial flora of the

hands was reduced by an average of 5.8 logs from baseline.

Dineen (Ref. 7) used a 7.5 percent povidone-iodine formulation as a

reference antiseptic in an open crossover evaluation of a health-care

personnel handwash drug product. Participation in the study followed a

1-week prewash period in which study subjects used only a bland

nonantiseptic soap. On day 1 of the study, samples were taken prior to

contamination and again after a second contamination followed by a 15-

second wash with a bland nonantiseptic soap, using the glove juice

sampling method. Following the post-wash sampling, subjects washed for

5 minutes with povidone-iodine to remove any remaining inoculum. The

hands of the first three subjects were contaminated with a 1 mL

inoculum containing 1 X 1014 S. marcescens, E. coli, P.

aeruginosa, and Providentia stuartii (P. stuartii). The hands of the

seven other subjects were contaminated with a 1 mL inoculum containing

8 X 1014 to 2 X 1015 S. marcescens and P. stuartii. Inocula

concentrations were determined each test day in a parallel experiment.

On days 3 or 4 and 5, the procedure was repeated except that subjects

were randomly assigned to wash with either (1) the reference antiseptic

or the test preparation or (2) were crossed over to the preparation not

used the previous day. In the interim between test days, subjects

followed the wash and sampling procedure using only the nonantiseptic

soap. The number of organisms included in the 1 mL inoculum was taken

as the baseline, and all reductions were calculated on this basis.

Neutralizers were incorporated in both the diluent and the culture

medium. When corrected for the average log reduction produced by the

nonantiseptic soap (4-log10), the reductions produced by povidone-

iodine ranged from 7 to 9 log10.

Studies conducted by Ulrich (Ref. 8) and Newsom and Matthews (Ref.

9) are supportive of the effectiveness of povidone-iodine for this

indication. Ulrich (Ref. 8) conducted a study using povidone-iodine 7.5

percent in 25 subjects. Both hands of each subject were contaminated

with a stock culture of Micrococcus roseus (2.75 x 108 organisms

per hand, the baseline count) and allowed to air dry for 60 seconds.

This artificial hand contamination was followed by a 15-second wash

with 5 mL of the povidone-iodine preparation, and this same procedure

was repeated until 25 contaminations/washes had been performed. Glove

fluid samples were taken after every fifth contamination/wash.

Dilutions of the glove fluid were made in a sterile diluent that

included a neutralizer. A neutralizer was also incorporated into the

culture medium. Based on the average of both hands, the povidone-iodine

preparation produced a 4.9 and a 5.2 log reduction of the transient

micro-organisms from baseline by the 5th and 10th wash, respectively.

By the end of the 25th wash the povidone-iodine preparation

demonstrated a 5.5 log10 reduction from the baseline bacterial

count.

Newsom and Matthews (Ref. 9) studied test solutions containing 5 or

10 percent povidone-iodine on hands artificially contaminated with an

overnight culture of E. coli. The numbers of micro-organisms were

measured before and immediately after hand disinfection with the test

solution in 15 subjects. Sampling of the hands was accomplished by

kneading the fingertips in a ``recovery'' broth that included a

neutralizer. A mean 4.4 log reduction from baseline was reported for

the bacterial counts taken immediately after the antiseptic wash.

Ayliffe, Babb, and Quoraishi (Ref. 10) evaluated the effect of

various detergent and alcoholic antiseptic formulations (including a

7.5 percent povidone-iodine formulation) on the removal of S. aureus,

Staphylococcus saprophyticus (S. saprophyticus), P. aeruginosa, or E.

coli from contaminated fingertips. In one set of experiments, six

subjects performed an initial wash with an unmedicated soap, followed

by the inoculation of the tips of the subjects' fingers and thumbs with

0.02 mL of a broth culture containing either S. aureus or P.

aeruginosa. Following contamination, subjects performed either a 30-

second wash with 5 mL of a detergent or alcoholic antiseptic

preparation, a 30-second wash with an unmedicated soap, or no wash at

all. Bacterial sampling was accomplished by rubbing the fingers and

thumbs on glass beads immersed in 100 mL of nutrient broth containing

neutralizers. All treatments were tested against each organism. Results

were reported as the log of the average number of viable organisms

recovered from each subject. Against S. aureus, povidone-iodine

produced a 3.2 log reduction, which was significantly superior to the

reduction achieved by the unmedicated soap. Against P. aeruginosa,

povidone-iodine produced a 2.7 log reduction. However, this was not

significantly different from the 2.2 log reduction demonstrated by the

unmedicated soap.

In a second set of experiments (Ref. 10), the same authors assessed

the effectiveness of three antiseptic formulations, including povidone-

iodine, and an unmedicated soap in the removal of S. aureus, S.

saprophyticus, or E. coli from contaminated fingertips. Under

conditions similar to those in the previous study, povidone-iodine

demonstrated a 3-log reduction in the baseline number of S. aureus,

which was significantly superior to the log reduction demonstrated by

the unmedicated soap. Povidone-iodine produced an average 2.1 log

reduction in the number of S. saprophyticus and a 2.8 reduction in the

number of E. coli. However, neither of these reductions was

significantly different from the reductions produced by the unmedicated

soap.

Rotter (Ref. 11) evaluated the influence of differences in two

testing methodologies on the demonstration of the effectiveness of

povidone-iodine. One test method used is the standard test method

(Vienna) for the evaluation of drug products for hygienic disinfection

adopted by the Austrian and German Societies for Hygiene and

Microbiology. In this test model, the release of E. coli from the

finger tips of artificially contaminated hands was determined before

and after a 1-minute wash with povidone-iodine. The second model, based

on agency recommendations for the testing of health-care personnel

handwashes, evaluated the release of the E. coli from all surfaces of

artificially contaminated hands by the glove juice sampling method

before and after a 1 minute wash with the ingredient. These comparisons

showed no significant difference in the reduction factor produced by

povidone-iodine when tested with the two methods. Povidone-iodine when

tested by the Vienna test method produced a 3.3 log10 reduction

from the baseline count. When tested by the second method, the

ingredient produced a 3.2 log10 reduction.

Rotter (Ref. 11) also used the Vienna test method to assess the

effectiveness of rubbing antiseptics onto the hands versus washing with

an antiseptic. Two povidone-iodine containing formulations were

included in the assessment. A watery solution of povidone-iodine with 1

percent available free iodine rubbed onto the skin produced a 4

log10 reduction. Washing with a detergent formulation of the

ingredient produced a 3.2 log10 reduction. However, this reduction

was not statistically different from the reduction produced by washing

with a nonantiseptic soap.

Rotter, Koller, and Wewalka (Ref. 12) used the Vienna test model to

assess the effectiveness of a povidone-iodine liquid soap preparation

(containing 0.75 percent available free iodine) for hygienic hand

disinfection. The subjects' hands were contaminated by immersing them

up to the mid-metacarpals in a broth culture of E. coli. The hands were

allowed to air dry for 3 minutes prior to a pretreatment sampling.

Sampling was accomplished by rubbing the finger tips of each hand for 1

minute on the bottom of a Petri dish containing a phosphate buffer

sampling solution with neutralizers. After a 2-minute wash with the

povidone-iodine or liquid soap followed by a 20-second rinse, the hands

were again sampled. Average log values of the counts from the right and

left hands of each subject were calculated, and the difference (log

reduction factor) was determined. The povidone-iodine liquid soap

formulation produced a 3.2 log10 reduction in the transient

organisms.

Wade and Casewell (Ref. 13) evaluated the residual effectiveness of

povidone-iodine against two clinical isolates associated with hospital

outbreaks of infection. An initial determination of the survival of the

test organisms on untreated hands of three subjects was made by

contaminating the subjects' finger tips with either of the test

organisms and sampling the individual fingers immediately after

contamination and at 1, 3, 10, and 30 minutes. The subjects' hands were

then pretreated by performing three 30-second washes at 5 minute

intervals with various alcoholic and aqueous antiseptic test

formulations, including a 7.5 percent povidone-iodine formulation and

an unmedicated bar soap. The contamination and sampling procedure was

repeated as before. All formulations were tested against both

organisms. The median value of the log counts for the three subjects as

each sampling was plotted against time. The survival curves for both

organisms on hands pretreated by washing with an unmedicated soap and

on hands with no pretreatment were similar. Pretreatment with povidone-

iodine resulted in counts that were consistently less than for the

untreated hands and for the hands pretreated by washing with an

unmedicated soap and water for both organisms. After 30 minutes, hands

pretreated with the povidone-iodine formulation demonstrated a 2.5

log10 reduction in the number of viable Enterococcus faecium and a

3.9 reduction in the number of viable Enterobacter cloacae.

The agency concludes that these data demonstrate the effectiveness

of povidone-iodine 5 to 10 percent for use as a health-care personnel

handwash.

Many published studies referenced in the submitted data and in the

published literature (Refs. 1 and 14 through 19) have evaluated the

effectiveness of povidone-iodine for use as a patient preoperative skin

preparation. Although the procedures followed are different from those

in the previous FDA testing procedures (43 FR 1210 at 1244) and from

those proposed in Sec. 333.470 of this amended tentative final

monograph, the essential criteria have been met.

Georgiade et al. (Ref. 15) evaluated the effectiveness of two

povidone-iodine formulations for use in the preoperative skin

preparation of 150 subjects scheduled for elective surgical procedures.

An initial sample for culture was taken from the unbroken skin of the

operation site prior to the use of the formulations, and a baseline

bacterial count was determined. Sampling was by a cup scrubbing method,

using a sterile wash solution that incorporated a neutralizer. The

operative site was then gently treated for 5 minutes with a povidone-

iodine surgical scrub formulation and allowed to dry. Following the

initial disinfection, a povidone-iodine antiseptic solution was evenly

applied to the site and allowed to dry. The sample site was rinsed with

sterile water and a second sample for culture was done. Upon completion

of surgical procedures lasting from 30 to 180 minutes, the sample site

was again cultured and sterile dressings were applied. The reported

mean post-scrub reduction in the baseline number of bacteria of the

sample site was 30,599 (4.5 log10 reduction). This reduction was

maintained through the surgery as evidenced by the reported post-

operative mean reduction of 30,613 organisms.

Vorherr, Vorherr, and Moss (Ref. 16) compared three antiseptic

preparations (including 10 percent povidone-iodine), in 150 female

subjects (50 to each preparation) for effectiveness in reducing the

numbers of bacteria in the perineum and groin. The mean log reductions

in bacteria after skin preparation with povidone-iodine at 10 minutes

and 3 hours, respectively, were reported as 3.65/3.09 for the perineum

and 3.42/2.85 for the groin. Another study by Dzubow et al. (Ref. 17)

evaluated three antiseptic skin preparations frequently used for

dermatologic surgical procedures. A 60-second wipe with 1-percent

povidone- iodine was performed in 14 subjects after which aerobic and

anaerobic cultures were taken at 5 and 60 minutes. The aerobic flora

were reduced by 2.8 and 2.5 log at 5 and 60 minutes, respectively. The

reduction in anaerobic flora was reported to be 1.7 log at 5 minutes

and 1.2 log at 60 minutes.

Leaper, Lewis, and Speller (Ref. 18) compared the effectiveness of

povidone-iodine impregnated drapes, povidone- iodine with a sterile

drape, and conventional preoperative skin preparation with povidone-

iodine for the reduction of skin bacteria. Forty-five subjects

scheduled to undergo elective groin surgery were randomized to one of

the three treatments. Impression plates and skin swabs were taken

immed

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