Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 71769 

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

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

1963 Comp., p. 389. 

§ 71.1 [Amended] 

■ 2. The incorporation by reference in 

14 CFR 71.1 of Federal Aviation 

Administration Order 7400.9R, Airspace 

Designations and Reporting Points, 

signed August 15, 2007, and effective 

September 15, 2007, is amended as 

follows: 

* * * * * 

Paragraph 6002 Class E Airspace 

Designated as Surface Areas. 

AAL AK E2 McGrath, AK [Revised] 

McGrath, McGrath Airport, AK 

(Lat. 62°57′10′′ N., long. 155°36′20′′ W.) 

That airspace within a 7.6-mile radius of 

the McGrath Airport. This Class E airspace 

area is effective during the specific dates and 

times established in advance by a Notice to 

Airmen. The effective date and time will 

thereafter be continuously published in the 

Airport/Facility Directory. 

* * * * * 

Paragraph 6005 Class E Airspace Extending 

Upward from 700 feet or More Above the 

Surface of the Earth. 

* * * * * 

AAL AK E5 McGrath, AK [Revised] 

McGrath, McGrath Airport, AK 

(Lat. 62°57′10′′ N., long. 155°36′20′′ W.) 

That airspace extending upward from 700 

feet above the surface within a 8.1-mile 

radius of the McGrath Airport and within 4 

miles north and 8 miles south of the 123° 

bearing from the McGrath Airport, AK 

extending from the 8.1-mile radius to 16 

miles southeast of the McGrath Airport, AK, 

and within 4 miles east and west of the 008° 

bearing from the McGrath Airport, AK, 

extending from the 8.1-mile radius to 11.2 

miles north of the McGrath Airport, AK; and 

that airspace extending upward from 1,200 

feet above the surface within a 74-mile radius 

of the McGrath Airport. 

* * * * * 

Issued in Anchorage, AK, on December 11, 

2007. 

Anthony M. Wylie, 

Manager, Alaska Flight Services Information 

Area Group. 

[FR Doc. E7–24410 Filed 12–18–07; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 201 

[Docket No. 1980N–0280] (formerly Docket 

No. 80N–0280) 

RIN 0910–AF44 

Over-the-Counter Vaginal 

Contraceptive and Spermicide Drug 

Products Containing Nonoxynol 9; 

Required Labeling 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is issuing a final 

rule establishing new warning 

statements and other labeling 

information for all over-the-counter 

(OTC) vaginal contraceptive drug 

products (also known as spermicides, 

hereinafter referred to as vaginal 

contraceptives or vaginal 

contraceptives/spermicides) containing 

nonoxynol 9 (N9). These warning 

statements will advise consumers that 

vaginal contraceptives/spermicides 

containing N9 do not protect against 

infection from the human 

immunodeficiency virus (HIV), the virus 

that causes acquired immunodeficiency 

syndrome (AIDS), or against getting 

other sexually transmitted diseases 

(STDs). The warnings and labeling 

information will also advise consumers 

that use of vaginal contraceptives and 

spermicides containing N9 can irritate 

the vagina and rectum and may increase 

the risk of getting the AIDS virus (HIV) 

from an infected partner. This final rule 

is part of FDA’s ongoing review of OTC 

drug products. FDA is issuing this final 

rule after considering public comments 

on its proposed regulation, and all 

relevant data and information on N9 

that have come to our attention. 

DATES: Effective Date: This rule is 

effective June 19, 2008. 

Compliance Date: The compliance 

date for all products subject to this final 

rule, including products with annual 

sales less than $25,000, is June 19, 2008. 

FOR FURTHER INFORMATION CONTACT: 

Arlene Solbeck, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 22, Silver Spring, 

MD 20993, 301–796–2090. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Background 

II. Comments on the Proposed Rule and 

FDA’s Responses 

A. Should N9 Remain Available as an 

Active Ingredient in OTC Vaginal 

Contraceptive Drug Products? 

B. What Issues Were Raised by 

Comments That Did Not Support 

the Proposed Warning Statements? 

1. Will Warning Labels Be Seen, 

Understood, or Followed? 

2. Are the Warnings Supported by the 

Scientific Literature? 

3. Is FDA Required To Prove Actual 

Causation To Justify the Warnings? 

C. Should Women Ask a Doctor 

Before Using N9 Products? 

D. Where Will the Warnings Appear 

in the Labeling? 

E. Where Will the Condom Usage 

Statement Appear in the Labeling? 

F. What Were the Comments on 

Condoms, Sexual Lubricants, and 

Barrier Methods? 

1. Do Warnings Apply to Condoms 

and Sexual Lubricants? 

2. Are Condoms Lubricated With N9 

Safe To Use? 

3. How Do Warnings Apply to N9 

Products Used With Barrier 

Methods? 

G. Is N9 Safe for Women at Low Risk 

for HIV/AIDS and STDs? 

H. Is N9 Safe for Rectal Use? 

I. Does N9 Increase the Risk of STDs 

Other Than HIV? 

J. What Issues Did Other Comments 

Discuss? 

1. Why Did FDA Define Frequent Use 

of N9 as ‘‘More Than Once a Day’’? 

2. Should ‘‘Pharmacist’’ or ‘‘Health 

Care Provider’’ Be Included on the 

Label? 

3. What Does ‘‘Unprotected Sex’’

Mean? 

4. What Does the Word ‘‘Irritation’’

Mean When Referring To ‘‘Vaginal 

Irritation’’ in the Warning 

Language? 

5. Should Warnings Be Printed in 

Both English and Spanish? 

III. FDA’s Final Conclusions on 

Warnings and Other Labeling 

Information for OTC Vaginal 

Contraceptive and Spermicide Drug 

Products Containing N9 

A. New Labeling Requirements 

B. Statement About Warnings 

IV. Analysis of Impacts 

V. Paperwork Reduction Act of 1995 

VI. Environmental Impact 

VII. Federalism 

VIII. References 

I. Background 

In the Federal Register of January 16, 

2003 (68 FR 2254), FDA (we) published 

a proposed rule (the proposed rule) to 

require new labeling warning statements 

for all OTC vaginal contraceptive drug 

products containing N9. These proposed 

warning statements are intended to 

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71770 Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 

advise consumers that vaginal 

contraceptives containing N9 do not 

protect against infection from HIV, the 

virus that causes AIDS, nor against 

getting other STDs. The warnings also 

would advise consumers that frequent 

use of vaginal contraceptives containing 

N9 can increase vaginal irritation, and 

that increased vaginal irritation from the 

use of N9 may increase the possibility 

of becoming infected with the AIDS 

virus (HIV) or other STDs from infected 

partners. The proposed rule contains the 

data and scientific evidence that we 

considered to require these warnings. 

N9 is a nonionic surfactant that works 

as a vaginal contraceptive (spermicide) 

by damaging the cell membrane of 

sperm. As stated in the proposed rule 

(68 FR 2254 at 2255), there are in vitro 

studies showing that N9 causes damage 

to the cell wall of certain STD pathogens 

and has activity against certain bacterial 

and viral STD pathogens, including 

HIV. Because N9 inhibits the replication 

of the AIDS virus (HIV) and other STD 

pathogens in vitro, it has been suggested 

over the years that N9 might help 

prevent or reduce the risk of 

transmission of the AIDS virus and 

other STDs in humans (68 FR 2254 at 

2255). Thus, research was undertaken to 

see if N9 would prevent HIV and STDs. 

In the proposed rule, FDA discussed the 

evidence that demonstrates that N9 does 

not prevent or reduce the risk of 

transmission of the AIDS virus and 

other STDs in humans (68 FR 2254 to 

2259). FDA also discussed recent 

scientific data that suggest that frequent 

use of N9 may increase the risk of HIV 

infection for women at risk for HIV (68 

FR 2254 to 2259). Thus, FDA issued the 

proposed rule to provide a clear, 

consistent message that N9 is not 

effective in preventing HIV 

transmission, and that N9 can facilitate 

transmission of the disease. We also 

proposed labeling (warnings and other 

information) to encourage the use of 

condoms as a method to help sexually 

active persons reduce the risk of 

becoming infected with the AIDS virus 

(HIV) and other STDs. We requested 

feedback on whether the proposed 

warnings adequately convey the safety 

concerns about N9 and whether there 

are additional data to support, expand, 

or refute the proposed warnings. 

In response to the proposed rule, we 

received 153 comments. Two comments 

were submitted from industry, 8 from 

consumer advocacy groups, 10 from 

health associations, 16 from health 

professionals, and 117 from individual 

consumers. These comments are on 

display in the Division of Dockets 

Management. For access to the docket to 

read background documents or 

comments received, go to http:// 

www.fda.gov/ohrms/dockets/ 

default.htm and insert the docket 

number (s), found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Division of Dockets 

Management, 5360 Fishers Lane, rm. 

1061, Rockville, MD 20852. We are 

responding to the comments, and 

discussing some additional data that has 

come to our attention, in this document. 

The majority of comments from 

consumers, consumer advocacy groups, 

health organizations, and health 

professionals supported FDA for 

proposing warnings for N9 vaginal 

contraceptive OTC drug products that 

inform consumers that N9 does not 

protect against HIV and other STDs and 

that frequent use (more than once a day) 

may increase the risk of infection of HIV 

from infected partners. The comments 

stated that the proposed warnings will 

inform consumers of the risks so that 

they can make responsible health care 

decisions. Forty-six consumers reported 

getting vaginal irritation, burning, 

itching, swelling, or increased yeast and 

urinary infections after using 

contraceptive products containing N9. 

These comments stated that the 

proposed labeling is necessary to warn 

consumers of the risks related to 

irritation associated with N9 and to 

educate consumers who mistakenly 

believe that vaginal contraceptives/ 

spermicides containing N9 also prevent 

STDs. 

Some comments did not support the 

proposed warnings. Other comments 

asked for clarification of the warning 

language, recommended changes in the 

wording of the warning language, or 

provided data to expand the proposed 

warnings. After reviewing the 

comments, FDA has revised the 

proposed warnings in this final rule. 

The differences between the warning 

language in the proposed and final rules 

are as follows: 

TABLE 1.—DIFFERENCES IN THE WARNING LANGUAGE IN THE PROPOSED AND FINAL RULES

Proposed Rule Final Rule 

‘‘For vaginal use only’’ ‘‘For vaginal use only 

Not for rectal (anal) use’’

We explain the reason for this change in section II.H, comment 12, of 

this document. 

‘‘Sexually transmitted diseases (STDs) alert: This product does not 

protect against the AIDS virus (HIV) or other STDs’’

‘‘Sexually transmitted diseases (STDs) alert: 

This product does not protect against HIV/AIDS or other STDs and 

may increase the risk of getting HIV from an infected partner’’

We discuss this change in section II.B.2, comment 3 of this document. 

‘‘Ask a doctor before use if you have 

• a new sex partner, multiple sex partners, or unprotected sex. Frequent use (more than once a day) of this product can increase vaginal 

irritation, which may increase the risk of getting the AIDS virus (HIV) 

or other STDs from infected partners. Ask a doctor or other health professional for your best birth control method.’’

‘‘Do not use if you or your sex partner has HIV/AIDS. If you do not 

know if you or your sex partner is infected, choose another form of 

birth control.’’

‘‘When using this product you may get vaginal irritation (burning, 

itching, or a rash)’’

We discuss these changes in sections II.B.2, comment 3 and II.C, 

comment 5 of this document. 

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Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 71771 

TABLE 1.—DIFFERENCES IN THE WARNING LANGUAGE IN THE PROPOSED AND FINAL RULES—Continued 

Proposed Rule Final Rule 

• ‘‘Studies have raised safety concerns that frequent use (more than 

once a day) of products containing nonoxynol 9 can increase vaginal 

irritation, which may increase the risk of getting the AIDS virus (HIV) 

or other STDs from infected partners. Vaginal irritation may include 

symptoms such as burning, itching, or a rash, or you may not notice 

any symptoms at all. If you use these products frequently and/or have 

a new sex partner, multiple sex partners or unprotected sex, see a 

doctor or other health professional for your best birth control and 

methods to prevent STDs.’’

• ‘‘studies have raised safety concerns that products containing the 

spermicide nonoxynol 9 can irritate the vagina and rectum. Sometimes this irritation has no symptoms. This irritation may increase the 

risk of getting HIV/AIDS from an infected partner’’

We discuss this change in section II.B.2, comment 3 of this document. 

• ‘‘you can use nonoxynol 9 for birth control with or without a diaphragm or condom if you have sex with only one partner who is not 

infected with HIV and who has no other sexual partners or HIV risk 

factors’’. 

We discuss this change in sections II.F.3, comment 10 and II.G, 

comment 11 of this document. 

• ‘‘use a latex condom without nonoxynol 9 if you or your sex partner 

has HIV/AIDS, multiple sex partners, or other HIV risk factors’’. 

We discuss this change in section II.F.2, comment 9 of this document. 

• ‘‘ask a health professional if you have questions about your best 

birth control and STD prevention methods’’. 

We discuss this change in section II.J.2, comment 15 of this document. 

• ‘‘correct use of a latex condom with every sexual act will help reduce the risk of getting the AIDS virus (HIV) and other STDs from infected partners’’. 

• ‘‘when used correctly every time you have sex, latex condoms 

greatly reduce, but do not eliminate, the risk of catching or spreading 

HIV, the virus that causes AIDS. 

We discuss this change in section II.F.1, comment 8 of this document. 

Use of N9 products may increase the risk of HIV and other STDs. Use of N9 products is associated with an increased risk of HIV.

We discuss this change in section II.I, comment 13 of this document. 

We describe and respond to the 

comments received in section II of this 

document. 

II. Comments on the Proposed Rule and 

FDA’s Responses 

A. Should N9 Remain Available as an 

Active Ingredient in OTC Vaginal 

Contraceptive Drug Products? 

(Comment 1) Some comments stated 

that N9 vaginal contraceptive drug 

products should be removed from the 

OTC market or changed from OTC to 

prescription status for the following 

reasons: 

• N9 does not protect against HIV or 

STDs. 

• N9 causes damage to the vaginal 

lining and increases the risk of 

contracting HIV due to this vaginal 

irritation. 

• Many new cases of HIV and STDs 

will develop if contraceptives with N9 

are available without consultation with 

a health professional. 

• Consumers who may not see, read, 

understand, or follow the advice 

contained on the warning labels need to 

be protected from the risks of using N9. 

They should have to see a health 

professional before using products 

containing N9. 

Some of these comments also suggested 

that, alternatively, manufacturers 

should be required to reformulate their 

products with other safe and effective 

spermicides or microbicides. 

Many other comments stated that N9 

products should remain an OTC 

contraceptive option for women at low 

risk for HIV infection for the following 

reasons: 

• N9 products are effective in 

preventing pregnancy, particularly 

when used with a barrier method such 

as a condom or diaphragm. 

• N9 products are a contraceptive 

option for women who cannot tolerate 

hormone-based birth control methods. 

• N9 products are a contraceptive 

option for women at low risk for HIV 

and STDs. 

• N9 products represent one of the 

few methods available for women that 

are controlled by women. 

• N9 products offer a ‘‘substantial’’

benefit to a ‘‘small but important’’ group 

of users. 

(Response) FDA does not agree that 

vaginal contraceptive drug products 

containing N9 should be removed from 

the OTC marketplace. As part of FDA’s 

review of the safety and effectiveness of 

this class of OTC drugs, the Advisory 

Review Panel on OTC Contraceptives 

and Other Vaginal Drug Products 

classified N9 as Category I (safe and 

effective) as a spermicide for the 

prevention of pregnancy on December 

12, 1980 (45 FR 82014 at 82028). 

Comments were received following 

publication of the panel’s report and 

additional scientific data became 

available. FDA published the proposed 

rule on OTC vaginal contraceptive drug 

products on February 2, 1995 (60 FR 

6892). In that proposed rule, FDA 

considered N9 safe as a vaginal 

contraceptive; however, data indicated 

that its effectiveness in final product 

formulations was highly variable. 

Therefore, FDA proposed clinical trials 

for N9 spermicidal products to validate 

their effectiveness in final formulations. 

In November 1996, four FDA advisory 

committees (Nonprescription Drugs, 

Reproductive Health Drugs, Antiviral 

Drugs, and Anti-infective Drugs) met to 

discuss the type and quality of data 

needed to support and ensure the 

spermicidal effectiveness of N9 in final 

formulations. The advisory committees 

concluded that the existing data 

provided evidence of some 

effectiveness, but they had concerns 

about variability in dose, different 

formulations, and duration of effect. The 

advisory committees recommended that 

FDA allow interim marketing of N9 

vaginal contraceptive drug products 

pending further clinical trials (68 FR 

2254 at 2255). 

Current data suggest that the number 

of women out of 100 who become 

pregnant in the first year of typical use 

of N9 spermicide drug products is as 

follows (Ref. 1): 

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71772 Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 

• 16 for the diaphragm with 

spermicide. 

• 16 to 32 (depending on whether the 

women have had prior births) for the 

cervical cap with spermicide. 

• 29 for spermicides alone (gel, 

cream, foam, film, suppository). 

The number of women who become 

pregnant using no contraception is 85 

out of 100 (Ref. 1). The Centers for 

Disease Control and Prevention (CDC) 

(Ref. 2) report that the combined use of 

diaphragms with N9 spermicide 

prevents approximately 460,000 

pregnancies in the United States each 

year. It is important to the public health 

that consumers have access to multiple 

methods of contraception to choose 

from that help prevent unplanned 

pregnancy. 

FDA is currently reviewing newly 

published data regarding the efficacy of 

N9 containing spermicides (Ref. 3), and 

we will publish our conclusions in a 

future issue of the Federal Register. 

These data are from a clinical trial 

which compares the effectiveness and 

safety of five spermicides, which 

include three gels containing 52.5 

milligrams (mg), 100 mg, and 150 mg of 

N9 per dose and a film and a 

suppository, each containing 100 mg of 

N9 per dose. In the meantime, based on 

its history of safety and effectiveness, 

we have determined that N9 should 

remain on the market while we 

complete our review. Based on the 

information currently available, we have 

also determined that women at low risk 

for HIV can safely use N9 products for 

their contraceptive needs and that the 

intervention of a doctor or health care 

provider is not necessary. 

B. What Issues Were Raised by 

Comments That Did Not Support the 

Proposed Warning Statements? 

1. Will Warning Labels Be Seen, 

Understood, or Followed? 

(Comment 2) Two comments stated 

that FDA’s proposed warnings may not 

adequately protect consumers against 

the health risks posed by N9 products 

because consumers may not see, read, 

understand, or follow the advice 

contained on the warning labels. One of 

the comments referred to a study 

sponsored by the National Council on 

Patient Information and Education 

(NCPIE), conducted in 2001, which 

surveyed adult consumers and health 

care professionals on the selfmedicating behaviors of the American 

public. The comment stated that the 

survey clearly established that 

consumers do not consistently read 

caution labels. The comment also 

mentioned a 1997 study by ‘‘Sansgiry et 

al.’’ of industry labeling practices which 

stated, according to the comment, that 

as the OTC package size increased, the 

font size used for the product increased, 

except that the font size for warnings 

remained constant. The comment stated 

that the study also showed that 22 

percent of the product packages 

examined used smaller than 6-point font 

type for warnings. The comment 

concluded from this study that 

consumers may have difficulty seeing 

and reading the N9 warning language. 

The second comment stated that many 

consumers consider OTC drug products 

to be safe and present no risks because 

they are available without a 

prescription. Thus, consumers may 

ignore the product labeling because of 

this false impression. The comment 

recommended that FDA use consumer 

surveys and focus groups to test for 

comprehension of the proposed labeling 

before publishing a final rule mandating 

specific language. 

(Response) FDA thinks that the 

warning statements for N9 vaginal 

contraceptive drug products will be 

seen, read, understood, and followed by 

consumers. We are aware of the studies 

cited by the comment, i.e., the Sansgiry, 

Cady, and Patil study (Ref. 4), which 

described OTC industry labeling 

practices at that time, and the NCPIE 

study (Ref. 5) that examined the selfmedicating behaviors of the American 

public, including what information 

consumers seek when reading an OTC 

drug product label. These studies 

reinforced the need for FDA to improve 

the OTC drug product label and also to 

enhance educational programs to teach 

consumers about the risks and benefits 

of OTC drugs. FDA issued new labeling 

requirements for OTC drug products on 

March 17, 1999 (64 FR 13254). This 

labeling regulation, codified in 21 CFR 

201.66, requires OTC drug products to 

be labeled with a standardized ‘‘Drug 

Facts’’ label. The ‘‘Drug Facts’’ label 

offers a more structured, organized, and 

compact presentation of the product 

information, which allows consumers to 

process the information with improved 

understanding, and provides clear 

signals regarding important information. 

The new requirements include a 6-point 

minimum type size, and bolded type 

headings and subheadings. When the 

warning requirements in this final rule 

for OTC vaginal contraceptive drug 

products containing N9 become 

effective, all manufacturers will be 

required to revise their label using the 

‘‘Drug Facts’’ format. Use of the revised 

labeling in the ‘‘Drug Facts’’ format will 

enable consumers to better read and 

understand the information presented 

and apply the information to the safe 

and effective use of OTC vaginal 

contraceptive drug products. 

Additionally, FDA is involved in 

various initiatives to encourage 

awareness of the safe and effective use 

of drugs and the importance of reading 

drug labels. FDA provides consumer 

articles, public service announcements, 

websites, etc., and also partners with 

many organizations to promote better 

understanding of the risks and benefits 

of drug products. For example, in 

cooperation with FDA, the Consumer 

Healthcare Products Association 

(CHPA) and NCPIE’s ‘‘Be MedWise’’

campaign provide information to 

consumers on the new OTC drug labels. 

2. ‘‘Are the Warnings Supported by the 

Scientific Literature?’’

(Comment 3) Three comments stated 

that FDA’s proposed warning language 

for N9 vaginal contraceptive drug 

products implies a link between the use 

of N9 and an increased risk of HIV that 

is not sufficiently supported by the 

scientific literature. These comments 

stated that the proposed warnings will 

frighten consumers in a manner that 

could affect the continued availability of 

a safe and effective contraceptive. The 

first comment contended that FDA 

relies primarily on two studies to 

support its position that there is a link 

between the use of N9 vaginal 

contraceptive drug products and an 

increased risk of HIV infection as 

follows: (1) The Van Damme et al. study 

(2002) (Ref. 6) and (2) the Kreiss et al. 

study (1992) (Ref. 7). The comment 

provided the following reasons why the 

Van Damme et al. study should not be 

used to support FDA’s proposed 

warnings for N9 products: 

• Twenty percent of the study 

subjects were lost to followup (so the 

investigators never determined the HIV 

status of these participants). 

• The results between the two test 

groups (N9 and placebo) were ‘‘barely’’

significant (p=0.047). 

• The placebo may have had a 

protective effect. 

• A much higher number of 

unprotected anal sex acts were reported 

from one of the study centers (Durban) 

where the most HIV seroconversions 

(conversions from HIV negative status to 

HIV positive status) occurred. 

The comment also contended that the 

Kreiss et al. study should not be used to 

support FDA’s proposed warnings for 

N9 products because: 

• The study was terminated early 

when it was determined that the HIV 

seroconversion results became 

inconsistent with the hypothesis that N9 

has a clinically beneficial effect in 

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Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 71773 

preventing HIV. The statistical analysis 

of the data at the time the study was 

terminated did not support a 

statistically significant conclusion that 

N9 increased the risk of HIV 

transmission. 

• The comparator product was 

changed midstream, indicating design 

problems. 

• More women had preexisting 

genital ulcers in the N9 test group, 

indicating randomization problems. 

• The sponge dosage form could raise 

safety issues not associated with other 

dosage forms. 

This comment added that FDA did not 

consider the results and conclusions of 

two other studies, Roddy et al. (1998) 

(Ref. 8) and Richardson et al. (2001) 

(Ref. 9). The comment stated that these 

studies either support a conclusion 

opposite to the Van Damme et al. and 

Kreiss et al. studies or weaken the 

conclusion that frequent use of N9 

vaginal contraceptives increases the risk 

of HIV infection from an infected 

partner. The comment concluded that 

the link between N9 use and an 

increased risk of HIV infection is 

speculation. The comment requested 

that FDA remove the following 

proposed warning language that links 

N9 use with an increased risk of HIV 

infection: 

• ‘‘Ask a doctor before use if you have 

a new sex partner, multiple sex 

partners, or unprotected sex. Frequent 

use (more than once a day) of this 

product can increase vaginal irritation, 

which may increase the risk of getting 

the AIDS virus (HIV) or other STDs from 

infected partners. Ask a doctor or other 

health professional for your best birth 

control method.’’

• ‘‘Studies have raised safety 

concerns that frequent use (more than 

once a day) of products containing 

nonoxynol 9 can increase vaginal 

irritation, which may increase the risk 

of getting the AIDS virus (HIV) or other 

STDs from infected partners. Vaginal 

irritation may include symptoms such 

as burning, itching, or a rash, or you 

may not notice any symptoms at all. If 

you use these products frequently and/ 

or have a new sex partner, multiple sex 

partners, or unprotected sex, see a 

doctor or other health professional for 

your best birth control and methods to 

prevent STDs.’’

The comment recommended the 

following language, which it contended 

more accurately reflects the known 

science and places the warnings in a 

more relevant context: 

• ‘‘Ask a doctor before use if you have 

frequent sex (more than three times a 

day). Frequent use (more than three 

times a day) of nonoxynol 9 may 

increase vaginal irritation, which may 

increase the risk of getting the AIDS 

virus (HIV) or other STDs from infected 

partners. Ask a doctor or other health 

professional for your best birth control 

method.’’

• ‘‘Studies concerning some 

nonoxynol 9 formulations (i.e., gel and 

sponge) in high risk populations (i.e., 

prostitutes) have raised very 

preliminary safety concerns that 

frequent use (more than three times a 

day) of products containing nonoxynol 

9 can increase vaginal irritation, which 

may increase the risk of getting the 

AIDS virus (HIV) or other STDs from 

infected partners. Other studies have 

shown no such risk for certain 

formulations (i.e., nonoxynol 9–

containing film and gel) in these high 

risk populations. Vaginal irritation may 

include symptoms such as burning, 

itching, or a rash, or you may not notice 

any symptoms at all. While there is no 

clear link between the frequent use of 

nonoxynol 9 and the increased risk of 

HIV infection or other STDs from 

infected partners, if you use these 

products frequently, see a doctor or 

other health professional for your best 

birth control and methods to prevent 

STDs.’’

The second comment stated that the 

Van Damme et al. study results are 

‘‘exploratory’’ and that the study’s 

‘‘generalizability’’ is a problem because 

the subjects were sex workers and had 

highly ‘‘atypical’’ sexual activity. This 

comment contended that previous trials 

of N9, conducted in sex workers, have 

shown conflicting results and, taken 

together, do not show a harmful or a 

protective effect. The third comment 

expressed similar concerns about the 

Van Damme study’s generalizability. 

(Response) FDA believes that the 

proposed warning language, which 

implies a link between frequent use of 

N9 vaginal contraceptive drug products 

and an increased risk of HIV, is 

supported by the scientific literature. As 

discussed elsewhere in this document, 

we are deleting the term ‘‘frequent’’

from the labeling requirements of this 

final rule because we believe that if a 

woman is at risk of HIV/AIDS, she 

should not be using N9 products, 

regardless of the frequency of use (see 

section J.1 of this document). In the 

proposed rule, FDA cited many studies 

that demonstrated that daily use of N9 

products causes vaginal irritation (i.e., 

inflammatory changes in the epithelial 

cells lining the vagina and disruption of 

these epithelial cells), and causes 

disruption of the vaginal flora (68 FR 

2254 at 2254 to 2258). Some studies 

suggested that the risk of these adverse 

events can be increased by frequent or 

chronic use of N9 products. In general, 

the various studies cited in the 

proposed rule defined infrequent or low 

frequency use as ‘‘use once a day or 

less.’’ It appears from these studies that 

infrequent use does not result in an 

increased rate of epithelial disruption. 

Therefore, FDA defined frequent use in 

the proposed rule as ‘‘more than once a 

day’’ and believes that the scientific 

literature supports the statement that 

frequent use (more than once a day) can 

increase vaginal irritation. 

In the proposed rule, FDA discussed 

studies that demonstrated that frequent 

use of N9 products causes increased 

disruption of the vaginal epithelium 

which may increase the risk of 

transmission of the AIDS virus (HIV). 

The most pivotal of these studies is the 

Van Damme et al. study (cited at 68 FR 

2254 at 2255) (Ref. 6). This was a 

randomized, placebo-controlled clinical 

trial to assess the effectiveness of a 

vaginal gel containing N9 on HIV–1 

transmission in female sex workers in 

Africa and Thailand, all at high risk for 

HIV. The study gel (COL–1492) 

contained 52.5 mg N9 (other 

constituents included a bioadhesive 

carbomer). The placebo gel differed 

from COL–1492 in that it did not 

contain N9 and had more carbomer. At 

enrollment, women received a supply of 

study gel (N9 or placebo) and male 

condoms to use until the next visit. 

Women were asked to return to the 

clinic every month for a follow-up visit. 

There was no limit on the number of gel 

doses that could be used per day. The 

primary endpoint of the study was 

incident HIV–1 infection. Secondary 

objectives included the effectiveness of 

this drug in prevention of chlamydial 

infection, gonorrhea, trichomoniasis, 

and genital ulcer disease, and safety and 

acceptability of the gel under situations 

of long-term use. The treatment period 

was 48 weeks. 

A total of 765 women were included 

in the primary analysis (376 in the N9 

group and 389 in the placebo group) and 

563 women completed the 48-week 

study. The overall retention rate of the 

participants in the study was 71 percent 

after 24 weeks and 68 percent after 48 

weeks, which is similar to rates 

projected by the study investigators for 

their sample size (60 percent retention 

per year). 

Of the 765 women, 59 in the N9 group 

and 45 in the placebo group 

seroconverted from HIV–1 negative to 

HIV–1 positive. Women who used an 

N9 vaginal gel had a significantly higher 

risk of becoming infected with HIV–1, 

compared with women using the 

placebo gel (p=0.047). The HIV–1 

incidence per 100 women-years was 

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71774 Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 

14.7 for the N9 group and 10.3 for the 

placebo group. This conclusion did not 

change when statistical adjustments 

were made for differences in the 

frequency of vaginal and anal sex not 

protected by condoms. 

To test the hypothesis of dosedependent toxic effects of N9, the 

investigators divided the mean gel use 

per working day into three categories 

based on tertiles. The investigators 

compared HIV–1 incidence per 

treatment group and per category of gel 

use. HIV–1 incidence increased with 

increasing gel use in the N9 group 

versus the placebo group. In the N9 

group, HIV–1 incidence rose from 8.8 

per 100 woman-years in women 

reporting mean use of 3.5 or fewer 

applicators per day to 30.6 in women 

reporting a higher mean daily use 

(hazard ratio 3.5; 95% Confidence 

Interval (CI) 2.1–5.8; p<0.0001). In the 

placebo group, HIV–1 incidence in 

those categories was 8.1 and 14.5 per 

100 woman-years, respectively (1.8; CI 

1.0–3.3, p=0.05). It is important to note 

that this analysis simply suggests a dose 

response between the amount of gel 

used per day and the risk of HIV–1 

infection. The data does not support a 

conclusion that using less than 3.5 

applications of N9 per day is associated 

with an incidence risk for HIV–1 

infection similar to placebo. Dividing 

the data by other methods (e.g., into 

quartiles), would identify other amounts 

of N9 per day supporting an association 

between the amount used and 

increasing risk. 

The study also investigated the 

frequency of N9 use and the incidence 

of lesions with epithelial breach, and 

whether the risk of HIV transmission 

increases with increasing number of 

lesions with epithelial breach. They 

found that the incidence of lesions with 

an epithelial breach rose with increasing 

gel use. The increase in incidence of 

lesions with an epithelial breach was 

seen in both the placebo and N9 groups, 

but it happened most rapidly in the N9 

group. 

FDA finds that one comment’s 

concern about certain aspects of the Van 

Damme et al. study are valid as follows: 

• There was a high loss to followup 

rate overall (retention rate was 68 

percent at 48 weeks). However, the 

study was designed with an assumption 

of an annual retention rate of 60 

percent. 

• There was a higher loss to followup 

rate in the N9 group compared to the 

placebo group. 

• The highest rates of both 

seroconversion and retention were 

observed at the largest center in the 

study (Durban). This center also 

reported the highest rate of anal sex. 

Although the study was not flawless, 

it was a large, well designed, 

randomized, placebo-controlled, multicenter clinical trial. Both the treatment 

and placebo groups were balanced with 

respect to baseline characteristics. Even 

with the noted limitations, we believe 

that the study is evidence that N9 may 

increase the risk of HIV–1 infection in 

a population already at increased risk 

for HIV–1 infection. 

The comment also expressed concerns 

about the Kreiss et al. study (Ref. 7) that 

we cited in the proposed rule (68 FR 

2254 at 2257). In this study, HIV 

negative sex workers in Nairobi, Kenya 

used either a vaginal sponge containing 

1,000 mg N9 or a placebo. Women using 

the N9 sponge had a higher conversion 

from HIV negative to HIV positive. A 

total of 21 women (43 percent) of the N9 

group and 19 women (35 percent) of the 

placebo group converted from HIV 

negative to HIV positive. We 

acknowledge the study’s shortcomings, 

as noted in the comment. However, we 

believe that early termination of the 

study for safety reasons (i.e., that the 

seroconversion results had become 

inconsistent with the hypothesis of 

clinically beneficial effects of N9 in 

preventing HIV seroconversion) was 

ethically appropriate, and suggests an 

outcome consistent with the results of 

the Van Damme et al. study. 

The comment contends that two other 

studies, Roddy et al. (Ref. 8) and 

Richardson et al. (Ref. 9), support a 

conclusion opposite to the Van Damme 

et al. and Kreiss et al. studies or weaken 

the conclusion that use of N9 

spermicide products may increase the 

risk of HIV infection from an infected 

partner. We do not agree. The Roddy et 

al. study was conducted to determine 

whether a 70-mg N9 vaginal film 

provided protection against HIV, 

gonorrhea, or chlamydia. The study 

population consisted of 1,170 HIVnegative female sex workers (575 in the 

placebo group, 595 in the N9 group) 

residing in Cameroon, Africa, who 

averaged at least 4 sexual partners per 

month. The study results showed no 

difference in the rate of HIV 

transmission in the N9 group versus the 

placebo group (48 vs. 46, respectively), 

although the incidence of genital lesions 

was slightly higher in the N9 group. The 

results from this study, while not 

consistent with the data from the Van 

Damme et al. study, do not invalidate 

the Van Damme et al. study results. 

Roddy et al. reported the total number 

of sexual acts for placebo and N9 users 

but did not report the average number 

of sexual acts per day or per week. 

There were 595 study participants in the 

N9 group who recorded a total of 

147,996 coital acts. The average length 

of study followup was 14 months. This 

averages out to 1 coital act every 1.7 

days. The study participants may not 

have used the N9 film often enough to 

demonstrate a difference in HIV risk 

compared to those using the placebo 

product. The results of the Roddy et al. 

study do not diminish the importance of 

the safety signal observed in the Van 

Damme et al. study. We believe that 

concerns about an increased risk of HIV 

transmission with frequent N9 use 

would apply to all products containing 

N9, regardless of the formulation. We do 

not agree with the comment’s suggestion 

that the proposed warnings be revised to 

read ‘‘Other studies have shown no such 

risk for certain formulations (i.e., N9 

film and gel) in these high risk 

populations’’. 

The Richardson et al. study was 

conducted to determine the effect of a 

52.5 mg N9 gel on the acquisition of 

STDs in HIV negative sex workers in 

Kenya. The study enrolled a relatively 

small number of subjects (total of 278 

women, 139 in the N9 group and 139 in 

the placebo group) at only one clinic 

site. The sample size and the low extent 

of exposure may not have been 

sufficient to detect rare events. The 

authors stated that women enrolled in 

the Richardson et al. study came from 

another ongoing prospective cohort 

study at the same clinic site. Selection 

of subjects from that study population 

might have introduced confounding 

factors into their study. There was 

relatively low frequency of sexual 

intercourse and exposure to the test 

products (median of twice a week). The 

median compliance with product use 

was 75 percent in the N9 group and 80 

percent in the placebo group (median 

compliance was 78 percent; the range 

was 0 to 100 percent). However, only 32 

percent of the women in the N9 group 

and 36 percent of the women in the 

placebo group were 100 percent 

compliant. It is not clear how reliable 

the data collection methods were. The 

study did not mention if women kept a 

diary of product use and frequency of 

sexual intercourse, or if this information 

was collected by the study staff during 

the follow-up visits. For all of these 

reasons, we conclude that this study 

cannot be reliably used to support the 

comment’s contentions. 

In conclusion, FDA does not accept 

the first comment’s request to remove 

the proposed warning language that 

links N9 use with an increased risk of 

HIV infection. FDA is providing 

information about whether it is safe for 

consumers to use these products based 

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Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 71775 

on their risk for HIV and STDs. Based 

on the available scientific evidence, we 

have determined that women should be 

advised that use of N9 can cause vaginal 

irritation and that use of N9 has been 

associated with an increased risk for 

HIV transmission in women at high risk 

for HIV/AIDS. Use of N9 can result in 

irritated and inflamed genital tissue and 

may increase a person’s risk of getting 

HIV/AIDS if they have sex with an HIV 

infected partner. We are, however, 

revising the proposed warnings to more 

clearly convey the message that N9 

spermicides cause vaginal irritation, 

may increase the risk of getting HIV 

from an infected partner, and should not 

be used by women at high risk for HIV/ 

AIDS. The warnings in § 201.325(b)(2) 

and (b)(3) of the proposed rule stated: 

• Sexually transmitted diseases 

(STDs) alert: 

This product does not protect against 

HIV/AIDS or other STDs 

• Ask a doctor before use if you have 

• a new sex partner, multiple sex 

partners, or unprotected sex. Frequent 

use (more than once a day) of this 

product can increase vaginal irritation, 

which may increase the risk of 

becoming infected with the AIDS virus 

(HIV) or other STDs from infected 

partners. Ask a doctor or other health 

professional for your best birth control 

method. 

The revised warnings in this final rule 

appear under the subheadings ‘‘Sexually 

transmitted diseases (STDs) alert,’’ ‘‘Do 

not use,’’ and ‘‘When using this 

product’’ and state: 

Sexually transmitted diseases (STDs) 

alert: This product does not protect 

against HIV/AIDS or other STDs and 

may increase the risk of getting HIV 

from an infected partner. 

Do not use if you or your sex partner 

has HIV/AIDS. If you do not know if 

you or your sex partner is infected, 

choose another form of birth control. 

When using this product you may get 

vaginal irritation (burning, itching, or a 

rash). 

We are also revising the additional 

labeling information in proposed 

§ 201.325(c)(1) (redesignated as 

§ 201.325(d)(1) in this final rule) to more 

accurately reflect the scientific literature 

and to convey the message that N9 

spermicides should not be used by 

women at risk for HIV. (Rectal use of N9 

is discussed later in section II.H, 

comment 12 of this document.) The 

revised additional labeling information 

states: 

• ‘‘Studies have raised safety 

concerns that products containing the 

spermicide nonoxynol 9 can irritate the 

vagina and rectum. Sometimes this 

irritation has no symptoms. This 

irritation may increase the risk of getting 

HIV/AIDS from an infected partner.’’

3. Is FDA Required To Prove Actual 

Causation to Justify the Warnings? 

(Comment 4) One comment stated 

that the proposed labeling implies a link 

between the use of N9 and an increased 

risk of HIV infection that is not 

sufficiently supported by the scientific 

literature. The comment contended that 

the link between N9 use and an 

increased risk of HIV transmission is 

‘‘mere speculation’’ that is not suggested 

by a comprehensive review of the 

scientific literature. In response to 

FDA’s statement that we need not show 

actual causation to mandate the 

proposed warning, the comment stated 

that it disputes a lesser standard unless 

FDA can show it will prevent a public 

harm. The comment suggested that there 

is not a public harm to prevent, so 

actual causation must be shown. The 

comment further asserted that the proof 

to require this warning must be 

sufficient to avoid a determination that 

the warning language requirement is 

arbitrary and capricious under 5 U.S.C. 

706, and suggested that FDA has not 

provided such proof. 

(Response) FDA disagrees with the 

comment. Based on a review of the 

available data, FDA believes the known 

scientific evidence supports its 

proposed warnings (see section II.B.2, 

comment 3 of this document). 

Furthermore, FDA does not need a 

causal relationship to be definitely 

established to mandate new warnings. 

To protect the public health, FDA has 

determined that the warnings are 

necessary to ensure that these OTC drug 

products continue to be safe and 

effective for their labeled indications 

under ordinary conditions of use as 

those terms are defined in the Federal 

Food, Drug and Cosmetic Act (the act). 

The warnings reflect FDA’s conclusion 

that there is reasonable evidence of a 

causal relation between a clinically 

significant hazard and the drug. 

Courts have upheld FDA’s authority 

to issue regulations requiring label 

warnings and other affirmative 

disclosures (see, e.g. Cosmetic, Toiletry 

and Fragrance Ass’n v. Schmidt, 409 F. 

Supp. 57 (D.D.C. 1976), aff’d without 

opn., Vic. No. 75–1715 (D.C. Cir., 

August 19, 1977), even in the absence of 

a proven cause-and-effect relationship 

between product usage and harm (see 

Council for Responsible Nutrition v. 

Goyan, Civ. No. 80–1124 (D.D.C. August 

1, 1980) (see also section III.B of this 

document). Mandating the warnings 

included in this final rule does not 

violate the Administrative Procedure 

Act’s prohibition against arbitrary and 

capricious conduct, because FDA’s 

action is reasonable based on the 

sufficiency of the available data and the 

need to protect the public health. 

C. Should Women Ask a Doctor Before 

Using N9 Products? 

(Comment 5) Some comments did not 

agree with FDA’s proposed warning 

language which advises women to ask a 

doctor before using N9 vaginal 

contraceptive drug products if they have 

a new sex partner, multiple sex 

partners, or unprotected sex. The 

comments questioned the need for 

women to consult physicians about the 

role of N9 in their pregnancy or STD 

prevention strategies. One comment 

doubted that the average physician 

could provide enough special expertise 

or insight about the role for N9 in a 

planned sexual encounter with a new 

partner to offset the inconvenience, 

discomfort, or cost of involving a health 

professional. Several comments stated 

that it was unclear what a woman 

should do before she is able to consult 

a physician (e.g., avoid sex, use 

alternative methods). Some comments 

contended that women should be given 

enough information in the labeling to 

empower them to act directly, without 

a health professional intermediary. 

These comments recommended 

replacing ‘‘Ask a doctor before use’’

with explicit statements such as 

‘‘Women who may be at risk of HIV and 

who plan to use the product more than 

once a day should consider another 

form of birth control’’ or ‘‘If you use 

these products more often than once a 

day and/or have a new sex partner, 

multiple sex partners, or unprotected 

sex you should consider another form of 

birth control’’. The comments suggested 

that adding a clarifying statement for 

women at low risk and a statement that 

reinforces the use of latex condoms is 

preferable to having consumers consult 

a physician for this information. 

(Response) FDA agrees with the 

comments that questioned the need for 

women to have to consult with a 

physician before using N9 vaginal 

contraceptive drug products if they have 

a new sex partner, multiple sex 

partners, or unprotected sex. We try to 

provide consumers with the appropriate 

information on the OTC drug product 

label to make informed decisions on the 

use of these products. We believe that, 

by revising the warning language under 

‘‘Ask a doctor before use if you have’’

and placing it under the subheadings 

‘‘Do not use’’ and ‘‘When using this 

product, ’’ consumers will be able to 

make appropriate decisions without 

consulting a physician. We consider this 

information particularly important for 

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71776 Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 

women who do not see a physician 

regularly, who will not consult a 

physician due to the expense, or who 

cannot get an appointment or 

consultation with a physician in a 

timely manner. Therefore, as discussed 

in section II.B.2, comment 3 of this 

document, we are revising the warnings 

under ‘‘Ask a doctor before use if you 

have’’ and placing them under the 

subheadings ‘‘Do not use’’ and ‘‘When 

using this product.’’

We are also revising the additional 

labeling information proposed in 

§ 201.325(c) to include more 

information about the use and safety of 

N9, so women will not have to consult 

a physician before use. We do not want 

to discourage consumers from speaking 

with physicians or other health care 

providers at any time about important 

health issues such as birth control and 

STD prevention. Therefore, we are 

including a statement in the additional 

labeling information that women should 

ask a doctor or other health professional 

for advice if they choose. The revised 

additional labeling statements are 

discussed in sections II.B.2, comment 3; 

II.F.1, comment 8; II.F.2, comment 9; 

II.F.3, comment 10; II.G, comment 11; 

and II.J.2, comment 15 of this document. 

D. Where Will the Warnings Appear in 

the Labeling? 

(Comment 6) Several comments 

addressed the placement of the 

proposed warning statements on the 

OTC package. The comments requested 

that FDA require prominent placement 

of the proposed warning statements on 

both the outer carton and package insert 

to warn consumers most effectively. 

One comment recommended using large 

and bold font to help attract the 

consumer’s attention and encourage 

reading of the package insert. 

(Response) FDA is requiring that the 

warning statements discussed in section 

II.B.2, comment 3 of this document 

(under the subheadings ‘‘Do not use’’

and ‘‘When using this product’’), the 

warning statements discussed in section 

II.H., comment 12 of this document 

(‘‘For vaginal use only’’ and ‘‘Not for 

rectal (anal) use’’), and the warning 

statement under the subheading ‘‘Stop 

use and ask a doctor if’’ (under 

§ 201.325(b)(4) in the proposed rule (68 

FR 2254 at 2262)), appear on the outside 

container or wrapper of the retail 

package, or on the immediate container 

label if there is no outside container or 

wrapper, in the Drug Facts labeling 

format, in accordance with 

§ 201.66(c)(7). We also proposed 

additional labeling information in 

§ 201.325(c) that could be placed either 

on the outside container or wrapper of 

the retail package, under the ‘‘Other 

information’’ section of the Drug Facts 

labeling, in accordance with 

§ 201.66(c)(7), or in a package insert. In 

this final rule, the revised condom usage 

statement, ‘‘when used correctly every 

time you have sex, latex condoms 

greatly reduce but do not eliminate the 

risk of catching or spreading HIV, the 

virus that causes AIDS.’’ must be 

located in the Drug Facts labeling under 

the heading ‘‘Other information’’ on the 

outside container or wrapper of the 

retail package. The rest of the additional 

labeling information now located in 

§ 201.325(d) of this final rule can be 

located on the outside container or 

wrapper of the retail package, under the 

‘‘Other information’’ section of the Drug 

Facts labeling in accordance with 

§ 201.66(c)(7), or in a package insert. In 

instances where the manufacturer 

chooses to provide a package insert for 

the additional information required in 

§ 201.325(d) of this final rule, FDA 

recommends that a bolded statement 

such as ‘‘before using this product read 

the enclosed package insert for complete 

directions and information’’ be included 

on the outside container or wrapper 

labeling to alert consumers and 

encourage reading of the package insert. 

E. Where Will the Condom Usage 

Statement Appear in the Labeling? 

(Comment 7) Several comments 

requested that the proposed condom 

message, ‘‘Correct use of a latex condom 

with every sexual act will help reduce 

the risk of getting the AIDS virus (HIV) 

and other STDs from infected partners,’’

should directly follow the STD alert on 

the outside container or wrapper as well 

as appear in a package insert so that 

consumers are immediately advised that 

STD/HIV protection is available OTC. 

(Response) FDA agrees with the 

comments that information about HIV/ 

STD protection (i.e., condom use) is 

important information and is now 

requiring that it be located on the 

outside container or wrapper in close 

proximity to the STD alert and other 

pertinent warnings. Because the 

information is not a warning, the 

statement appears in the Drug Facts 

labeling, under the heading ‘‘Other 

information.’’ In addition, we are 

revising the condom usage statement 

(see section II.F, comment 8 in this 

document). 

F. What Were the Comments on 

Condoms, Sexual Lubricants, and 

Barrier Methods? 

1. Do Warnings Apply to Condoms and 

Sexual Lubricants? 

(Comment 8) Some comments 

questioned whether FDA’s proposed 

warnings apply to the labeling of 

condoms lubricated with N9. Several 

comments noted that women using 

condoms and sexual lubricants 

containing N9 may have a risk similar 

to those women using vaginal 

contraceptives and so both groups need 

to receive the same warnings. Some of 

these comments stated that FDA should 

propose warning language similar to the 

proposed warnings for vaginal 

contraceptive products for condoms and 

sexual lubricants containing N9, 

because of the substantial public health 

risk posed by N9 containing products 

when used rectally. 

(Response) This final rule requiring 

warnings for all OTC vaginal 

contraceptives/spermicides containing 

N9 applies to drug products. It does not 

apply to condoms lubricated with N9, 

which are primarily regulated as 

medical devices (not drugs). Through 

rulemaking, spermicidal condoms were 

classified as Class II medical devices (21 

CFR 884.5310) and, as such, FDA’s 

Center for Devices and Radiological 

Health (CDRH) has primary jurisdiction 

over their regulation. 

Although this final rule does not 

apply to condoms lubricated with N9, it 

does contain information for consumers 

about using condoms as a method to 

help reduce the risk of becoming 

infected with the AIDS virus (HIV) and 

other STDs. In the January 16, 2003, 

proposed rule, FDA discussed the 

public health benefit of such 

information and proposed the following 

condom usage statement for spermicides 

containing N9: ‘‘Correct use of a latex 

condom with every sexual act will help 

reduce the risk of getting the AIDS virus 

(HIV) and other STDs from infected 

partners’’ (see 68 FR 2254 at 2258 to 

2259 and 2262). Subsequently, FDA 

reviewed the labeling of condoms (with 

and without N9) and issued a revised 

draft guidance (Ref. 10) on condom 

labeling. Therefore, FDA revised the 

proposed condom usage statement to be 

consistent with the statement it 

recommended in this new guidance. 

The new revised condom usage 

statement (in § 201.325(c) in this final 

rule) reads: ‘‘[bullet] when used 

correctly every time you have sex, latex 

condoms greatly reduce, but do not 

eliminate the risk of catching or 

spreading HIV, the virus that causes 

AIDS.’’

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Vaginal moisturizers and vaginal 

sexual lubricants are currently being 

evaluated under the OTC drug review 

regulatory process. FDA issued a call for 

data notice on December 31, 2003 (68 

FR 75585), requesting safety and 

effectiveness data on various products, 

including vaginal moisturizers and 

vaginal lubricants. FDA will publish its 

findings in a future issue of the Federal 

Register. 

2. Are Condoms Lubricated With N9 

Safe to Use? 

(Comment 9) Some comments stated 

that labeling products containing N9 

with a warning that usage promotes the 

transmission of HIV or other STDs may 

cause sexually active individuals to 

question whether or not to use a 

condom at all. One comment expressed 

concern that after reading FDA’s 

proposed warnings, consumers would 

perceive that condoms lubricated with 

N9 were not safe and would use nothing 

rather than use a condom containing 

N9. Therefore, several comments stated 

that the labeling should remind 

consumers that N9 is still effective in 

reducing unwanted pregnancies and 

that we should continue to endorse the 

use of spermicidal condoms. One of the 

comments stated that condoms 

containing N9 provide important 

consumer and public health care 

benefits, because N9 in condoms is 

intended to provide a secondary means 

of pregnancy prevention if the condom 

is used incorrectly or breaks. 

Other comments were not supportive 

of N9 condoms. One comment requested 

that FDA take action to address the 

health risks posed by N9 as an additive 

to condoms and sexual lubricants by 

withdrawing them from the 

marketplace. This comment stated that 

N9 is not necessary to the function of 

lubricants and, in the case of condoms, 

N9 is not necessary as an additive or 

lubricant to their function as a physical 

barrier against pregnancy and disease. 

Several comments stated that the correct 

and consistent use of condoms provides 

excellent protection against pregnancy 

and HIV even without the addition of 

N9. One comment concluded that since 

N9 lubricated condoms and sexual 

lubricants containing N9 offer no 

proven benefit to any user group, and 

pose substantial risks to some users, the 

risk should be eliminated rather than 

relying on a ‘‘labeling’’ solution. One 

comment suggested revising the 

proposed condom statement to read 

‘‘Correct use of a (dry) latex condom, (or 

a silicone lubricated latex condom, but 

NOT a condom lubricated with N9) with 

every vaginal sexual act will help 

reduce the risk of transmitting the AIDS 

virus (HIV) and other STDs.’’

(Response) As discussed in section 

II.F.1, comment 8 of this document, this 

rulemaking does not apply to condoms 

that contain N9. It does, however, 

provide for information to be added to 

labeling to inform consumers about 

using condoms as a method to help 

reduce the risk of becoming infected 

with the AIDS virus (HIV) and other 

STDs. In section II.F.1, comment 8 of 

this document, FDA discussed a 

condom usage statement to encourage 

the use of condoms as a method to help 

reduce the risk of becoming infected 

with the AIDS virus (HIV) and other 

STDs as proposed in the proposed rule. 

In the revised draft guidance on condom 

labeling (Ref. 10) discussed previously, 

FDA recommended the additional 

warning ‘‘if you or your partner has 

HIV/AIDS, or you do not know if you 

or your partner is infected, you should 

choose a latex condom without N-9’’. 

Because FDA wishes to provide 

consistent information to consumers 

regarding products that contain N9, we 

are including a new labeling statement 

in § 201.325(d)(3) for vaginal 

contraceptive drug products containing 

N9 to read as follows: ‘‘[bullet] use a 

latex condom without nonoxynol 9 if 

you or your sex partner has HIV/AIDS, 

multiple sex partners, or other HIV risk 

factors.’’

3. How Do Warnings Apply to N9 

Products Used With Barrier Methods? 

(Comment 10) Some comments were 

concerned with how FDA’s proposed 

warnings apply to consumers using an 

N9 spermicide product with barrier 

methods. The comments pointed out 

that FDA’s proposed warning language 

for vaginal contraceptive drug products 

containing N9 applies to spermicide use 

alone, and not to concurrent use of N9 

with female barrier methods. The 

comments stated concerns about how 

consumers who use N9 products with 

female barrier methods (such as 

diaphragms and cervical caps) would 

apply FDA’s proposed warning language 

to their use. Several comments stated 

that consumers are currently advised 

(e.g., in product labeling or by 

physicians) to use spermicide with 

diaphragms and cervical caps to 

improve contraceptive effectiveness and 

to insert more spermicide (without 

removal of the diaphragm or cervical 

cap) if repeat intercourse occurs. The 

comments stated that FDA’s proposed 

labeling does not provide clear advice 

for women (particularly those at low 

risk for HIV) who use these barrier 

methods. These comments contend that 

there is not enough data about the 

effectiveness of diaphragms or caps 

without additional spermicide to 

recommend discontinuation of the 

spermicide. Some comments also stated 

that FDA’s proposed warning language 

may deter promotion and use of female 

barrier methods that require additional 

spermicide. One of these comments 

stated that a recent report from the CDC 

(Ref. 2) estimates that N9 used together 

with diaphragms prevents 460,000 

pregnancies each year. The comment 

stated that the proposed warning 

language would have a harmful effect on 

women’s health by increasing 

unintended pregnancies and even STDs 

among women who would otherwise 

safely use cervical barriers plus N9, but 

might switch to a less effective method 

or no method at all. Another comment 

stated that clinicians may advise lowrisk clients not to use N9 as an adjunct 

to diaphragm use, which may result in 

more unintended pregnancies. One 

comment suggested that FDA advise 

consumers in the labeling that the 

studies that have found risks associated 

with the use of N9 did not study the 

products with a diaphragm or cervical 

cap. 

(Response) Currently, FDA approved 

directions for use for cervical caps (Ref. 

11) and diaphragms (21 CFR 884.5350) 

specify use of a spermicide with these 

devices. FDA believes that women using 

cervical caps or diaphragms with N9 

products are exposed to the same risks 

as women who use N9 vaginal 

contraceptive drug products alone 

because of the nature of the risk. The 

warning and other labeling information 

statements that are required by this final 

rule will inform women how best to use 

N9 spermicidal jellies and creams with 

barrier contraceptive methods. 

FDA agrees with the comments that 

women at low risk for HIV should be 

able to safely use barrier methods along 

with N9 products and should not be 

advised to change from a barrier 

contraceptive method. There have been 

several studies over the years of cervical 

caps and diaphragms using N9 that have 

shown minimal irritation to the vagina 

and cervical mucosa (Refs. 12, 13, and 

14). It is important to note that these 

were contraceptive studies among 

women in stable, monogamous 

relationships and that typical subjects 

did not use the devices multiple times 

a day. In section II.G, comment 11 of 

this document, we discuss labeling 

revisions that advise women at low risk 

for HIV that N9 products continue to be 

safe for contraception for them. 

Accordingly, FDA is also including 

barrier method and condom users at low 

risk for HIV in these statements. 

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G. Is N9 Safe for Women at Low Risk for 

HIV/AIDS and STDs? 

(Comment 11) A number of comments 

stated that women at low risk for HIV 

and STDs should continue to use N9 

spermicides as a contraceptive option. 

One comment stated that some women 

who use N9 containing vaginal 

contraceptive drug products for birth 

control may face a different (lower) STD 

risk profile than the women studied in 

the clinical trials, who were at a higher 

risk for HIV infection. The comment 

stated that the proposed warnings might 

exert a harmful net effect on women’s 

health by increasing unintended 

pregnancy and STDs among women 

who would otherwise use N9 products 

safely, but might switch to less effective 

methods or no method at all because of 

the warnings. The comment urged that 

the data need to be properly 

extrapolated to women at lower risk for 

HIV who now use N9 products to 

successfully prevent pregnancy. 

Another comment stated that until FDA 

has additional data on the safety of N9 

in low risk settings, women currently 

using N9 containing spermicides for 

birth control should continue to do so. 

Similarly, some comments stated that 

women at high risk for HIV infection 

should not use N9 products for 

contraception, but that these products 

should remain a contraceptive option 

for women at low risk. These comments 

stated that if a woman is not at high risk 

for HIV (because she is in a mutually 

monogamous relationship with a HIV 

negative partner), then use of N9 

products poses less of a safety hazard. 

Thus, the comments contended that 

women at low risk for HIV could safely 

use N9 products multiple times in a 

single day. 

One comment stated that FDA should 

qualify the warning language regarding 

‘‘frequent use’’ for women who are at no 

or low risk for HIV. The comment 

suggested that FDA add the following 

qualifying statements to the labeling: 

‘‘Women at low risk of HIV (i.e., those 

in a mutually monogamous relationship 

with an HIV negative partner) can safely 

use nonoxynol 9 (with or without a 

diaphragm) on multiple intercourse 

occasions in a single day. Frequent use 

of nonoxynol 9 is only problematic for 

women exposed to HIV and other 

STDs.’’ A similar comment stated that 

FDA must carefully word the warnings 

to provide consumers with the ability to 

accurately assess the risks associated 

with the product’s use. 

(Response) FDA agrees that many 

women who use N9 vaginal 

contraceptive and spermicide drug 

products containing N9 have lower STD 

and HIV risk profiles than the women 

studied in some of the clinical trials 

discussed in the proposed rule (68 FR 

2254) (e.g., the Van Damme et al. study). 

We also agree that frequent use of N9 

products poses no risk of HIV 

transmission for an HIV negative 

woman who is in a mutually 

monogamous relationship with an HIV 

negative partner. We believe that a 

woman in such a relationship would not 

suffer any harm, other than incurring 

vaginal irritation or epithelial lesions, 

from frequent use of N9. Accordingly, 

we are revising the additional labeling 

information proposed in § 201.325(c)(1) 

(redesignated as § 201.325(d)(2) in this 

final rule) to include a new statement 

advising women that they can continue 

to use N9 vaginal contraceptive and 

spermicide drug products if they are at 

low risk for HIV. The statement reads: 

‘‘[bullet] you can use nonoxynol 9 for 

birth control with or without a 

diaphragm or condom if you have sex 

with only one partner who is not 

infected with HIV and who has no other 

sexual partners or HIV risk factors.’’

H. Is N9 Safe for Rectal Use? 

(Comment 12) Ten comments urged 

FDA to require a warning against the 

rectal use of vaginal contraceptive drug 

products containing N9. This is because 

N9 causes serious damage to the rectal 

epithelium that may increase the risk of 

getting HIV or other STDs. The 

comments stated that although the 

products are designed for vaginal 

contraceptive use, they are routinely 

used for lubrication and (mistakenly) for 

protection against STDs during anal 

intercourse. The comments stated that 

these products are used rectally not only 

by the male homosexual population, but 

also by heterosexual couples who 

engage in both vaginal and anal 

intercourse. Two comments cited survey 

studies (Refs. 15 and 16) showing that 

the routine use of these products within 

the homosexual male population 

continues, due to the prevailing 

misperception that N9 protects against 

infection by sexually transmitted 

pathogens. Gross et al. (Ref. 15) 

surveyed 3,093 gay men from 6 U.S. 

cities who reported having anal 

intercourse during the previous 6 

months. Of the 2,953 men in the study 

who used lubricants during anal 

intercourse, 41 percent actively sought 

N9 containing products. In another 

survey study conducted in San 

Francisco and Oakland in 2001 by 

Mansergh et al. (Ref. 16), 41 percent (79) 

of 193 men who had anal sex with men 

during the previous year used an N9 

product without a condom. The men 

stated that they believed that N9 

provided some protection against HIV 

transmission. The comment stressed 

that these data were collected after the 

CDC and the San Francisco Department 

of Health issued warnings about the 

dangers of using N9 rectally. 

In further support of warnings against 

rectal use of N9, the comments referred 

to several studies in animals (Refs. 17 

and 18) and one study in humans (Ref. 

19) that showed that rectal application 

of N9 products causes damage to the 

cells lining the rectum. The comments 

stated that this damage may 

compromise a barrier that protects 

against viral and bacterial infection, 

thereby increasing the risk of HIV 

transmission. One comment suggested 

the following warning: ‘‘Products 

containing Nonoxynol–9 should never 

be used rectally; to do so may 

substantially increase one’s risk of 

contracting HIV from an infected 

partner.’’ Another comment requested 

that a warning against rectal use be 

placed on the outer carton as well as in 

the package insert. 

(Response) FDA agrees that products 

containing N9 should not be used 

rectally. The studies provided by the 

comments show that the rectal use of N9 

damages the rectal epithelium in both 

animals and humans (Refs. 17, 18, and 

19). One study in mice (Ref. 17) showed 

that pretreating the rectums of the mice 

with 2-percent N9 or with spermicide 

products containing N9 before 

inoculation with herpes simplex virus 2 

(HSV–2) increased the likelihood of 

infection and shortened the time until 

infection. In this study, the rectal 

epithelium appeared to be repaired by 1 

hour. The investigators stated that 

although they chose to use HSV–2, the 

results could be generalized to HIV 

transmission in humans because mouse 

and human epithelia are 

morphologically similar and because the 

same type of target cells of HIV, 

mononuclear blood cells, are present in 

the connective tissue and become more 

numerous after tissue damage. A study 

in monkeys (Ref. 18) investigated the 

effect of multiple applications of a 4- 

percent N9 product, placebo gel, or no 

product in three groups of monkeys. 

Each group receiving test product or 

placebo gel got 1 daily intrarectal 

application for 3 consecutive days, at 24 

hour intervals. Before each treatment, 

animals were given a saline 

(pretreatment) rectal lavage. Test 

product was recovered by rectal lavage 

15 minutes after administration. 

Examination of rectal lavage samples 

indicated an increase in the presence of 

epithelial cells and sheets of epithelium 

15 minutes after N9 application, as 

compared with placebo gel and nomstockstill on PROD1PC66 with RULES

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product groups. The investigators noted 

that 1 day after the first exposure, 

epithelial sloughing was no longer 

evident, suggesting that repair had 

occurred rapidly. However, the 

investigators noted the continued 

presence of sloughed epidermal sheets 

24 hours after repeated product 

application, indicating a cumulative 

effect of N9 on rectal tissues. 

In a small study in humans, Phillips 

et al. (Ref. 19) investigated the effects of 

rectal application of two OTC products 

containing 2-percent and 1-percent N9, 

respectively, and two control 

formulations (not containing N9) in four 

subjects (three men, one woman). The 

experimental procedures were selfadministered. After a baseline saline 

rectal lavage, the four formulations were 

evaluated by placing each test 

formulation in the rectum for 15 

minutes via a syringe, at a minimum of 

72 hours between test formulations. 

After 15 minutes and again 8 to 10 

hours later, rectal lavage was performed. 

The investigators showed that the rectal 

lavage collected 15 minutes after N9 

application revealed sheets of 

epithelium. 

Sheets of rectal epithelium were not 

present in lavage fluid collected 8 to 12 

hours later, or after treatment with 

control formulations. The authors 

concluded that N9 caused rapid 

exfoliation of the rectal epithelium in 

humans, which is likely to make users 

more susceptible to HIV infection. 

Recently, Phillips et al. (Ref. 20) 

studied the effects of rectal use of an 

OTC vaginal contraceptive drug product 

containing 2-percent N9 in 18 human 

subjects. Thirteen of the study 

participants underwent rectal 

evaluation at baseline and then at 15 

minutes or at 2 hours after N9 treatment. 

The remaining study participants 

underwent rectal evaluation at 8 hours 

after treatment. A physician applied the 

test formulation and did the rectal 

evaluation, which included biopsies as 

well as lavage. The investigators 

observed sheets of epithelium in lavage 

specimens collected at 15 minutes after 

N9 treatment. They observed less 

material in specimens collected at 2 

hours, but what they collected appeared 

to be degraded cells and bacteria. In 

specimens collected at 8 hours there 

was no evidence of cellular material. 

Similarly, biopsies collected at 15 

minutes appeared to be different from 

baseline biopsies; the epithelial tissue 

appeared missing or separated from the 

underlying submucosa. At 2 and 8 hours 

after treatment, the epithelium appeared 

similar to the baseline specimens, 

suggesting that the epithelium can 

repair itself within 2 hours. The 

investigators concluded that N9 use 

should be avoided during anal sex, 

because the rectal epithelium, which is 

rapidly exfoliated after a single use of 2- 

percent N9, protects HIV target cells in 

the submucosa from HIV infection. 

We conclude that these data 

demonstrate that N9 is an irritant to 

cells lining the rectum. The rectal 

epithelial damage that occurs with N9 

exposure could increase the risk of 

getting HIV from an infected partner. 

Furthermore, a one-time rectal 

application of N9 is sufficient to cause 

rapid sloughing of extensive areas of the 

rectal epithelium. Accordingly, FDA is 

requiring a warning to inform users that 

these products should not be used 

rectally. This warning is required to be 

prominently displayed on the outside 

container or wrapper of the retail 

package or the immediate container 

label if there is no outside container or 

wrapper, in accordance with the 

requirements of § 201.66(c). The 

warning states: ‘‘Not for rectal (anal) 

use’’ [in bold type]. This warning 

follows the warning that reads ‘‘For 

vaginal use only’’ [in bold type]. In 

addition, as discussed in section II.B.2, 

comment 3 of this document, we are 

revising the additional labeling 

proposed in § 201.325(c)(1) to convey 

the message that studies show that N9 

can irritate the vagina and rectum and 

that this may increase the risk of getting 

HIV/AIDS from an infected partner. 

I. Does N9 Use Increase the Risk of STDs 

Other Than HIV? 

(Comment 13) Two comments 

contended that there is no evidence that 

N9 increases the risk of getting other 

STDs, such as Neisseria gonorrhea 

(gonorrhea) and Chlamydia trachomatis 

(chlamydia). The comments asked FDA 

to delete all referrals to a possible 

increased risk of getting STDs other than 

HIV in its proposed warnings for vaginal 

contraceptive drug products containing 

N9. 

(Response) FDA agrees. While the Van 

Damme et al. study (Ref. 6) suggested 

that frequent use of N9 increased the 

risk of HIV infection compared with use 

of placebo in the population studied, it 

did not show sufficient evidence of an 

increased risk of gonorrhea or 

chlamydia infection. FDA is not aware 

of evidence suggesting a link between 

N9 use and increased risk of STDs other 

than HIV at this time. Accordingly, we 

are revising the warnings for N9 vaginal 

contraceptive and spermicide drug 

products to delete any reference to a 

possible increased risk of getting STDs 

other than HIV when N9 is used by 

people at risk for these infections. 

However, this does not affect the 

warning, which we retain, that N9 does 

not protect against HIV or other STDs. 

J. What Issues Did Other Comments 

Discuss? 

1. Why Did FDA Define Frequent Use of 

N9 as ‘‘More Than Once a Day’’? 

(Comment 14) Many comments 

addressed the definition of ‘‘frequent 

use’’ in the proposed warning language 

for N9 containing vaginal contraceptive 

drug products. FDA recommended that 

‘‘frequent use’’ be defined as ‘‘more than 

once a day.’’ Several comments stated 

that this definition is reasonable. One 

comment pointed out that many normal 

men and women from ‘‘middle 

America,’’ not just prostitutes, have sex 

several times a day with their partners, 

and these consumers need to be 

protected from the risks of using N9. 

Other comments stated that FDA’s 

rationale for proposing ‘‘frequent use’’

as ‘‘more than once a day’’ is unclear. 

One comment contended that in the Van 

Damme et al. study (Ref. 6), in which 

investigators concluded that there was a 

statistically significant increase in the 

risk of HIV infection from infected 

partners, N9 gel use was ‘‘more than 3.5 

times a day.’’ The comment stated that 

when the product was used less 

frequently than 3.5 times a day, there 

was no difference in risk of HIV 

transmission between the N9 and 

placebo users. 

Therefore, the comment stated that 

the definition of frequent use should be 

changed to ‘‘no more than 3 times a 

day.’’ One comment contended that in 

the Van Damme et al. study, subjects 

averaged 3.6 coital acts a day, with a 

mean of 70 sexual acts a month, which 

is atypical of the sexual activity for the 

majority of women worldwide. Some 

comments questioned whether the 

results for commercial sex workers in 

Africa and Thailand can be reasonably 

extrapolated to the general U.S. 

population and questioned how the 

proposed definition of frequent use, 

‘‘more than once a day’’ was 

extrapolated from the study data. 

Other comments claimed that 

frequent use, defined as ‘‘more than 

once a day,’’ overstates the risk for many 

women and seems very restrictive. One 

comment proposed that women be 

informed that low frequency use of N9 

products has not been shown to increase 

HIV infection rates, though it may 

increase vaginal irritation. Another 

comment stated that if a woman is not 

at risk for HIV, then frequent use of N9 

poses no additional hazard. The 

comment proposed that women at low 

risk for HIV could safely use N9 several 

times in a single day. 

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71780 Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 

(Response) FDA proposed to define 

frequent use as ‘‘more than once a day’’

because studies cited in the proposed 

rule (68 FR 2254 at 2257 to 2258) 

showed that if N9 is used more than 

once a day, the risk of vaginal irritation 

and epithelial lesions increases. When 

this occurs, the risk of HIV infection 

from infected partners increases 

according to studies discussed in the 

proposed rule (68 FR 2254 at 2258). The 

one comment erroneously concludes 

from the Van Damme et al. study that 

the risk was only present if women used 

N9 more than 3.5 times per day. As 

noted previously, the investigators 

analyzed dose response by dividing N9 

use into categories based on tertiles. The 

use category of greater than 3.5 times 

per day identified the lower limit of the 

upper tertile. The analysis does not 

identify a dose below which there is not 

an increased risk. We are not aware of 

any available data to assist us in 

identifying a dose of N9 where there is 

no increased risk for HIV–1 infection in 

a susceptible population. Because of the 

nature of the risk, we believe that if a 

woman is at risk for HIV/AIDS, she 

should not be using N9 products, 

regardless of the frequency of use. 

In this final rule, we are eliminating 

references to ‘‘frequent use’’ and 

revising the warning statements as 

described in section II.B.2, comment 3 

of this document. We also agree with 

the comments that if a woman is not at 

risk for HIV, then frequent use of N9 

poses no additional hazard of HIV 

infection. Thus, women at low risk for 

HIV can use N9 for birth control, with 

or without a diaphragm or condom, 

regardless of frequency. Accordingly, 

we are revising the labeling information 

to include a statement for women at low 

risk for HIV/AIDS (see section II.G, 

comment 11 of this document). It is also 

important to note that as explained in 

the response to section II.B.2, comment 

3 of this document, the comment 

regarding risk only being present if 

women used N9 more than 3.5 times a 

day is erroneous. 

2. Should ‘‘Pharmacist’’ or ‘‘Health Care 

Provider’’ Be Included on the Label? 

(Comment 15) Some comments 

requested that the proposed warnings 

that begin with the words ‘‘Ask a 

doctor’’ and ‘‘Stop use and ask a doctor’’

be revised to include ‘‘health care 

provider,’’ because consumers receive 

health information from providers other 

than doctors. Other comments suggested 

that FDA include the term 

‘‘pharmacists’’ in the labeling because 

pharmacists are the most accessible 

health providers for consumers. 

(Response) In this final rule, we 

revised the warnings proposed after the 

subheading ‘‘Ask a doctor before use if 

you have’’ and moved them to after the 

subheadings ‘‘Do not use’’ and ‘‘When 

using this product.’’ Therefore, whether 

the subheading states ‘‘Ask a doctor 

before use’’ or ‘‘Ask a health care 

provider before use’’ is moot. Regarding 

the use of the terms ‘‘doctor’’ and 

‘‘health care provider’’ in the 

subheadings ‘‘Ask a doctor before use if 

you have’’ and ‘‘Stop use and ask a 

doctor if,’’ FDA addressed this issue in 

the final rule for labeling of OTC human 

drugs (64 FR 13254 at 13261 to 13262). 

FDA acknowledged that in addition to 

physicians, other licensed professionals 

play an important role in delivering 

clinical services directly to consumers. 

FDA decided not to endeavor to list 

each specific practitioner who is 

licensed and qualified and decided that 

‘‘doctor’’ is sufficiently broad and 

inclusive for this warning. Nonetheless, 

we are including in the ‘‘Other 

information’’ statements in § 201.325(d) 

of this final rule, a statement that 

contains the term ‘‘health professional’’

and advises women to ask a ‘‘health 

professional’’ if they have questions 

about their birth control and STD 

prevention methods. The statement 

reads: ‘‘[bullet] ask a health professional 

if you have questions about your best 

birth control and STD prevention 

methods’’. 

3. What Does ‘‘Unprotected Sex’’ Mean? 

(Comment 16) Several comments 

questioned use of the words 

‘‘unprotected sex’’ in the proposed 

warning language. The comments asked 

FDA to clarify whether ‘‘unprotected 

sex’’ means sex without a condom or 

sex without birth control. 

The comments contended that the 

words ‘‘unprotected sex’’ are confusing 

in the proposed ‘‘Other information’’

statement ‘‘if you use these products 

frequently and/or have a new sex 

partner, multiple sex partners, or 

unprotected sex, see a doctor or other 

health professional for your best birth 

control and methods to prevent STDs’’

because sex with N9 is not unprotected 

sex. One comment recommended using 

the words ‘‘unprotected vaginal 

intercourse.’’ Another comment 

recommended replacing ‘‘unprotected 

sex’’ with the phrase ‘‘sex without 

condoms.’’

(Response) FDA agrees that the 

wording ‘‘unprotected sex’’ could be 

clearer. As discussed in sections II.B.2., 

comment 3, II.C., comment 5, II.F.2., 

comment 9, II.F.3., comment 10, II.G., 

comment 11 and II.J.2., comment 15 of 

this document, FDA revised the 

wording of the warnings and ‘‘Other 

information’’ statements and the words 

‘‘unprotected sex’’ are no longer used. 

4. What Does the Word ‘‘Irritation’’

Mean When Referring To ‘‘Vaginal 

Irritation’’ in the Warning Language? 

(Comment 17) Two comments 

recommended that FDA not use the 

term ‘‘irritation’’ when referring to 

‘‘vaginal irritation’’ in the warning 

language. The comments stated that 

epithelial disruption and inflammation 

can occur in the absence of perceived 

symptoms of irritation. Therefore, 

women who do not perceive what they 

believe is ‘‘irritation’’ might mistakenly 

believe they are safe from N9 hazards. 

The comments suggested that the 

proposed warning language (‘‘Frequent 

use (more than once a day) of this 

product may increase vaginal irritation, 

which may increase the risk of getting 

the AIDS virus (HIV) or other STDs from 

infected partners’’) be revised to read 

‘‘Frequent use of this product (more 

than once a day) can damage the cells 

lining the vagina, a condition that may 

increase one’s risk of becoming infected 

with HIV or other STDs if exposed to an 

infected partner.’’

(Response) FDA understands the 

comments’ concerns, but considers the 

term ‘‘irritation’’ the proper term to use 

in the warning language. This term is 

used throughout the scientific literature 

to describe the effects of N9 on the 

vaginal epithelia. Because ‘‘irritation’’ is 

also used widely in educational 

literature written for consumers, we 

believe that this term has more meaning 

for consumers than ‘‘damage to the cells 

lining the vagina.’’ We recognize that 

vaginal irritation may be asymptomatic; 

therefore, to protect women at risk for 

HIV, we advise them in § 201.325(b) in 

this final rule not to use N9 

contraceptive products at all. We are 

also including in the ‘‘Other 

information’’ statements in § 201.325(d) 

of this final rule a statement that advises 

women that sometimes this irritation 

has no symptoms. 

5. Should Warnings Be Printed in Both 

English and Spanish? 

(Comment 18) One comment stated 

that it would be helpful to have 

warnings in Spanish as well as English 

on the package label and the package 

insert, with toll-free numbers and/or 

internet websites so that consumers may 

obtain additional data or clarification. 

(Response) FDA allows manufacturers 

to print their package label and labeling 

in languages other than English. 

However, manufacturers must adhere to 

certain requirements in 21 CFR 

201.15(c)(1), (c)(2), and (c)(3). Thus, 

FDA permits a dual label, e.g., a 

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complete English label can be 

accompanied with a complete label in 

Spanish, side by side. A package insert 

can be printed in English on one side, 

and Spanish on the other. Also, 

manufacturers may include toll-free 

numbers and internet websites in 

product labeling. If a manufacturer 

wants to include this type of 

information within the Drug Facts box, 

it must be done in accordance with 

§ 201.66(c)(9). 

III. FDA’s Final Conclusions on 

Warnings and Other Labeling 

Information for OTC Vaginal 

Contraceptive and Spermicide Drug 

Products Containing N9 

A. Labeling Requirements 

FDA is amending part 201 (21 CFR 

part 201) by adding § 201.325 entitled 

‘‘Over-the-counter drugs for vaginal 

contraceptive and spermicide use 

containing nonoxynol 9 as the active 

ingredient; required warnings and 

labeling information.’’ This section will 

require new warnings and other labeling 

information for all OTC vaginal 

contraceptive and spermicide drug 

products containing N9 as the active 

ingredient, whether marketed under a 

New Drug Application (NDA) or the 

ongoing OTC drug review. The required 

warnings must be prominently 

displayed on the outside container or 

wrapper of the retail package, or the 

immediate container label if there is no 

outside container or wrapper, in 

accordance with the requirements of 

§ 201.66(c), FDA’s labeling regulation 

(Drug Facts) for OTC drug products. 

FDA is requiring that the following new 

warnings be added to the labeling of all 

marketed OTC vaginal contraceptive/ 

spermicide drug products containing 

N9: 

1. Under the heading ‘‘Warnings’’ the 

warning ‘‘Not for rectal (anal) use’’ [in 

bold type]’’ will follow the warning 

‘‘For vaginal use only’’ [in bold type]. 

2. Under the heading ‘‘Warnings’’ the 

warning ‘‘Sexually transmitted diseases 

(STDs) alert [in bold type]: This product 

does not [this word in bold type] protect 

against HIV/AIDS or other STDs and 

may increase the risk of getting HIV 

from an infected partner’’. 

3. Under the subheading ‘‘Do not 

use,’’ the warning ‘‘Do not use [in bold 

type] if you or your sex partner has HIV/ 

AIDS. If you do not know if you or your 

sex partner is infected, choose another 

form of birth control.’’

4. Under the subheading ‘‘When using 

this product,’’ the warning ‘‘When using 

this product [in bold type][optional, 

bullet] you may get vaginal irritation 

(burning, itching, or a rash)’’. 

5. Under the subheading ‘‘Stop use 

and ask a doctor if,’’ the warning ‘‘Stop 

use and ask a doctor if [in bold 

type][optional, bullet] you or your 

partner get burning, itching, a rash, or 

other irritation of the vagina or penis.’’

FDA is also requiring additional 

labeling information. This information 

is to appear either on the outside 

container or wrapper of the retail 

package, under the ‘‘Other information’’

section of the Drug Facts labeling in 

accordance with § 201.66(c)(7), or in a 

package insert. The only exception is 

the statement in § 201.325(c) about the 

correct use of latex condoms, which 

must appear on the outside container or 

wrapper of the retail package or the 

immediate container label if there is no 

outside container or wrapper, under the 

‘‘Other information’’ section of the 

‘‘Drug Facts’’ labeling. The additional 

labeling information is as follows: 

• ‘‘studies have raised safety concerns 

that products containing the spermicide 

nonoxynol 9 can irritate the vagina and 

rectum. Sometimes this irritation has no 

symptoms. This irritation may increase 

the risk of getting HIV/AIDS from an 

infected partner’’. 

• ‘‘you can use nonoxynol 9 for birth 

control with or without a diaphragm or 

condom if you have sex with only one 

partner who is not infected with HIV 

and who has no other sexual partners or 

HIV risk factors’’. 

• ‘‘when used correctly every time 

you have sex, latex condoms greatly 

reduce, but do not eliminate, the risk of 

catching or spreading HIV, the virus that 

causes AIDS. [this information must 

appear on the outside container or 

wrapper labeling in the Drug Facts 

labeling under ‘‘Other information’’]. 

• ‘‘use a latex condom without 

nonoxynol 9 if you or your sex partner 

has HIV/AIDS, multiple sex partners, or 

other HIV risk factors’’. 

• ‘‘ask a health professional if you 

have questions about your best birth 

control and STD prevention methods’’. 

FDA is also recommending that all of 

the required warnings and other 

labeling information be included in a 

package insert. Many marketed OTC 

vaginal contraceptive and spermicide 

drug products already have a package 

insert that contains information on how 

to use the product, and this new 

information could readily be 

incorporated in the package insert. 

The following is an example of the 

Drug Facts labeling (for content 

purposes only) for a vaginal 

contraceptive/spermicide drug product 

containing N9 that incorporates all of 

the required new warnings and labeling 

information on the Drug Facts label. The 

quantity of active ingredient per dosage 

unit, the font sizes for title, headings, 

subheadings, condensed text, and 

bullets, and other graphic features, must 

be in accordance with § 201.66. 

BILLING CODE 6111–01–S 

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71782 Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 

BILLING CODE 6111–01–C 

B. Statement About Warnings 

Mandating warnings in an OTC drug 

product regulation does not require a 

finding that any or all of the OTC drug 

products covered by the regulation 

actually caused an adverse event, and 

FDA does not so find. Nor does FDA’s 

requirement of warnings repudiate the 

prior OTC drug monographs and 

regulations under which the affected 

drug products have been lawfully 

marketed. Rather, as a consumer 

protection agency, FDA has determined 

that warnings are necessary to ensure 

that these OTC drug products continue 

to be safe and effective for their labeled 

indications under ordinary conditions 

of use as those terms are defined in the 

act. This judgment balances the benefits 

of these drug products against their 

potential risks. (See 21 CFR 330.10(a).) 

FDA’s decision to act in this instance 

need not meet the standard of proof 

required to prevail in a private tort 

action (Glastetter v. Novartis 

Pharmaceuticals Corp., 252 F.3d 

986,991 (8th Cir. 2001)). To mandate 

warnings, or take similar regulatory 

action, FDA need not show, nor do we 

allege, actual causation. For an 

expanded discussion of case law 

supporting FDA’s authority to require 

such warnings, see the December 6, 

2002 (67 FR 72555), final rule entitled 

‘‘Labeling of DiphenhydramineContaining Drug Products for Over-theCounter Human Use.’’

IV. Analysis of Impacts 

In accordance with Executive Order 

12866, FDA has previously analyzed the 

potential economic effects of this final 

rule. As announced in the proposal, the 

agency has determined that the rule is 

not a significant regulatory action as 

defined by the Order. The agency has 

not received any new information or 

comments that would alter its previous 

determination. 

FDA has examined the impacts of this 

final rule under Executive Order 12866, 

the Regulatory Flexibility Act (5 U.S.C. 

601–612), and the Unfunded Mandates 

Reform Act of 1995 (Public Law 104–4). 

Executive Order 12866 directs agencies 

to assess all costs and benefits of 

available regulatory alternatives and, 

when regulation is necessary, to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). The 

agency believes this final rule is not a 

significant regulatory action under 

Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because the one-time costs to 

comply with this rule are small, the 

agency certifies that the final rule will 

not have a significant economic impact 


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Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 71783 

1 The annual PPI for pulp, paper, and allied 

products (the major cost driver for labeling) rose by 

16.4 percent between 1998 and 2005 (from 174.1 to 

202.6) http://data.bls.gov/cgi-bin/surveymost, 

extracted December 5, 2006. (FDA has verified the 

Web site address, but we are not responsible for 

subsequent changes to the Web site after this 

document publishes in the Federal Register.) 

2The original values from the uniform label 

formats rule (64 FR 13254), inventory loss between 

$500 and $3,000 and a weighted average of $2,050, 

were inflated by 16.4 percent. 3In the proposal for this rule, the estimated total 

one-time cost of relabeling was reported in error as 

$266,000, the actual value should have been 

$226,000. 4In the proposed rule this value was reported as 

$321,000, but should have been $281,200. 

on a substantial number of small 

entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $127 

million, using the most current (2006) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this final rule to result in any 1-year 

expenditure that would meet or exceed 

this amount. 

The purpose of this final rule is to 

require additional labeling for OTC 

vaginal contraceptive and spermicide 

drug products containing N9. The 

labeling includes new warnings and 

other important information about using 

these products. These products are 

currently packaged in an outer carton 

that should have sufficient space to 

accommodate this additional labeling. 

FDA is aware that most of the currently 

marketed products already include a 

consumer package insert. Therefore, to 

allow firms greater flexibility, FDA is 

allowing some of the new information to 

appear in the package insert. There are 

a limited number of products currently 

marketed that will be affected by this 

final rule, and the incremental one-time 

costs are minimal. The one-time costs 

include designing the new carton, 

designing a new package insert, and the 

inventory loss of any unused current 

labeling. FDA assumes the same 

weighted average cost to relabel, 

inflated to reflect current dollars, that it 

estimated for the final rule requiring 

uniform label formats of OTC drug 

products (64 FR 13254 at 13279 to 

13281) (i.e., $3,600 x 1.1641 ($4,190) per 

stock keeping unit (SKU) (individual 

products, packages, and sizes)). 

Inventory loss was estimated using data 

from a study supporting the previously 

mentioned rule. With a 6-month 

implementation period, inventory loss 

was estimated to be between $582 and 

$3,492 per SKU, depending on product 

sales, for an estimated weighted average 

inventory loss of $2,386. The inventory 

loss and redesign costs for the package 

insert are estimated to be about $1,606 

per SKU2. 

FDA’s Drug Listing System identifies 

15 manufacturers and distributors of 

OTC vaginal contraceptive and 

spermicide drug products containing N9 

that together produce approximately 40 

SKUs. At a relabeling cost of $4,190 per 

SKU and an inventory loss of $2,386 per 

SKU, estimated total one-time cost of 

relabeling would be $263,040 (40 x 

($4,190 + $2,386))3. Even if all required 

wording is revised on the outer carton, 

manufacturers may revise their package 

inserts as well to conform to the revised 

language. This adds another $64,240 (40 

x $1,606) to the one-time cost, for an 

estimated total of $327,2804. 

As FDA is providing the language of 

the labeling to be used, all firms should 

have the necessary skills and personnel 

to perform the required relabeling either 

in-house or by contractual arrangement. 

The final rule does not require any new 

reporting or recordkeeping activities. No 

additional professional skills are 

needed. 

About 9 firms affected by this final 

rule meet the Small Business 

Administration’s definition of a small 

entity (fewer than 750 employees). The 

actual impact on these firms will vary 

depending on the number and nature of 

the products they manufacture or 

distribute. All nine entities market 

additional types of products and have 

only one or two SKUs affected by this 

final rule. The average incremental cost 

per SKU to comply with this final rule 

is estimated to be $8,182 ($327,280/40 

SKUs). Actual costs to the small entities 

will likely be lower because distributors 

of low sales volume OTC drug products 

usually market their products in 

packaging that costs less than the 

industry average. 

While the costs to individual 

manufacturers to relabel their products 

are minimal, the potential benefits to 

consumers who use these products are 

substantial. FDA considers it essential 

that users be aware that these products 

do not protect against the AIDS virus 

(HIV) or other STDs. The monetary 

benefit of potentially preventing any 

cases of AIDS or STDs is significant 

compared to the minor cost of relabeling 

these products to provide the new 

required information. 

FDA considered but rejected several 

labeling alternatives: (1) A shorter or 

longer implementation period, and (2) 

an exemption from coverage for small 

entities. FDA considers it important that 

this information appear in product 

labeling as soon as possible, but 

acknowledges that implementation in a 

timeframe any less than 6 months 

would be very difficult for affected 

manufacturers. However, because of the 

importance of this new labeling 

information, FDA considers a period of 

12 months too long to implement this 

new labeling. FDA rejected an 

exemption for small entities because the 

new labeling is also needed by 

consumers who purchase products 

marketed by those entities. 

The analysis shows that this final rule 

is not economically significant under 

Executive Order 12866 and that FDA 

has considered the burden to small 

entities. Based on this analysis, FDA 

does not believe manufacturers will 

incur a significant economic impact. 

Therefore, FDA certifies that the final 

rule will not have a significant 

economic impact on a substantial 

number of small entities. No further 

analysis is required under the 

Regulatory Flexibility Act (5 U.S.C. 

605(b)). 

V. Paperwork Reduction Act of 1995 

FDA concludes that the labeling 

requirements in this document are not 

subject to review by the Office of 

Management and Budget because they 

do not constitute a ‘‘collection of 

information’’ under the Paperwork 

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

et seq.). Rather, the labeling statements 

are a ‘‘public disclosure of information 

originally supplied by the Federal 

government to the recipient for the 

purpose of disclosure to the public’’ (5 

CFR 1320.3(c)(2)). 

VI. Environmental Impact 

FDA has determined under 21 CFR 

25.31(a) that this action is of a type that 

does not individually or cumulatively 

have a significant effect on the human 

environment. Therefore, neither an 

environmental assessment nor an 

environmental impact statement is 

required. 

VII. Federalism 

FDA has analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that the rule will have a 

preemptive effect on State law. Section 

4(a) of the Executive order requires 

agencies to ‘‘construe * * * a Federal 

statute to preempt State law only where 

the statute contains an express 

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71784 Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 

preemption provision or there is some 

other clear evidence that the Congress 

intended preemption of State law, or 

where the exercise of State authority 

conflicts with the exercise of Federal 

authority under the Federal statute.’’

Section 751 of the the act (21 U.S.C. 

379r) is an express preemption 

provision. Section 751(a) of the act (21 

U.S.C. 379r(a)) provides that: ‘‘* * * no 

State or political subdivision of a State 

may establish or continue in effect any 

requirement— * * * (1) that relates to 

the regulation of a drug that is not 

subject to the requirements of section 

503(b)(1) or 503(f)(1)(A); and (2) that is 

different from or in addition to, or that 

is otherwise not identical with, a 

requirement under this Act, the Poison 

Prevention Packaging Act of 1970 (15 

U.S.C. 1471 et seq.), or the Fair 

Packaging and Labeling Act (15 U.S.C. 

1451 et seq.).’’

Currently, this provision operates to 

preempt States from imposing 

requirements related to the regulation of 

nonprescription drug products. (See 

section 751(b) through (e) of the act for 

the scope of the express preemption 

provision, the exemption procedures, 

and the exceptions to the provision.) 

This final rule would establish new 

warning statements and other labeling 

for all OTC vaginal contraceptive drug 

products. Although this final rule would 

have a preemptive effect, in that it 

would preclude States from 

promulgating requirements related to 

labeling for OTC vaginal contraceptive 

drug products that are different from or 

in addition to, or not otherwise identical 

with a requirement in the final rule, this 

preemptive effect is consistent with 

what Congress set forth in section 751 

of the act. Section 751(a) of the act 

displaces both State legislative 

requirements and State common law 

duties. We also note that even where the 

express preemption provision is not 

applicable, implied preemption may 

arise. See Geier v. American Honda Co., 

529 US 861 (2000). 

FDA believes that the preemptive 

effect of the final rule would be 

consistent with Executive Order 13132. 

Section 4(e) of the Executive order 

provides that ‘‘when an agency proposes 

to act through adjudication or 

rulemaking to preempt State law, the 

agency shall provide all affected State 

and local officials notice and an 

opportunity for appropriate 

participation in the proceedings.’’ FDA 

provided the States with an opportunity 

for appropriate participation in this 

rulemaking when it sought input from 

all stakeholders through publication of 

the proposed rule in the Federal 

Register of January 16, 2003 (68 FR 

2254). FDA received comments from 

three State groups on the proposal and 

considered those comments in drafting 

this final rule. 

In addition, on May 12, 2006, FDA’s 

Division of Federal and State Relations 

provided notice via fax and email 

transmission to elected officials of State 

governments and their representatives 

of national organization. The notice 

provided the States with further 

opportunity for input on the rule. It 

advised the States of the publication of 

the proposed rule and encouraged State 

and local governments to review the 

notice and to provide any comments to 

the docket (Docket No. 1980N–0280 

(formerly Docket No. 80N–0280)), 

opened in the January 16, 2003, Federal 

Register proposed rule, by a date 30 

days from the date of the notice (i.e., by 

June 12, 2006), or to contact certain 

named individuals. FDA received no 

comments in response to this notice. 

The notice has been filed in the above 

numbered docket. 

In conclusion, the agency believes 

that it has complied with all of the 

applicable requirements under the 

Executive order and has determined that 

the preemptive effects of this rule are 

consistent with Executive Order 13132. 

VIII. References 

The following references are on 

display in the Division of Dockets 

Management, 5630 Fishers Lane, rm 

1061, Rockville, MD 20852, under 

Docket No. 1980N–0280, and may be 

seen by interested persons between 9 

a.m. and 4 p.m., Monday through 

Friday. 

1. Hatcher R. A. et al., Contraceptive 

Technology, 18th revised ed., Ardent 

Media, New York, NY, p. 792, 2004. 

2. CDC, ‘‘Nonoxynol–9 Spermicide 

Contraception Use—United States, 

1999,’’ Morbidity and Mortality Weekly 

Report, 51(18):389–392, 2002. 

3. Raymond, E., P. Chen, and J. Luoto, 

‘‘Contraceptive Effectiveness of Five 

Nonoxynol–9 Spermicides: A 

Randomized Trial,’’ Obstetrics and 

Gynecology, 103:430–439, 2004. 

4. Sansgiry, S. S., P. S. Cady, and S. 

Patil, ‘‘Readability of Over-the-Counter 

Medication Labels,’’ Journal of the 

American Pharmaceutical Association, 

NS37(5):522–528, 1997. 

5. A National Survey of Consumers 

and Health Professionals: ‘‘Attitudes 

and Beliefs About the Use of Over-theCounter Medicines: A Dose of Reality,’’

prepared for The National Council on 

Patient Information and Education 

(NCPIE), www.harrisinteractive.com, 

2002. 

6. Van Damme, L. et al., 

‘‘Effectiveness of COL–1492, A 

Nonoxynol–9 Vaginal Gel, on HIV–1 

Transmission in Female Sex Workers: A 

Randomized Controlled Trial,’’ The 

Lancet, 360:971–977, 2002. 

7. Kreiss, J. et al., ‘‘Efficacy of 

Nonoxynol 9 Contraceptive Sponge Use 

in Preventing Heterosexual Acquisition 

of HIV in Nairobi Prostitutes,’’ Journal 

of the American Medical Association, 

268:477–482, 1992. 

8. Roddy, R. E. et al., ‘‘A Controlled 

Trial of Nonoxynol 9 Film to Reduce 

Male-to-Female Transmission of 

Sexually Transmitted Diseases,’’ New 

England Journal of Medicine, 

339(8):504–510, 1998. 

9. Richardson, B. A. et al., 

‘‘Evaluation of a Low-Dose Nonoxynol 9 

Gel for the Prevention of Sexually 

Transmitted Diseases, a Randomized 

Trial,’’ Sexually Transmitted Diseases, 

28:394–400, 2001. 

10. FDA, Draft Guidance for Industry 

and FDA Staff: Class II Special Controls 

Guidance Document: Labeling for Male 

Condoms Made of Natural Rubber Latex, 

Center for Devices and Radiological 

Health (CDRH), 2005. 

11. FDA, FemCap Barrier 

Contraceptive, User Manual and 

Instructions for Use, 2003. 

12. Bounds, W. et al., ‘‘The 

Diaphragm With and Without 

Spermicide: A Randomized, 

Comparative Efficacy Trial,’’ Journal of 

Reproductive Medicine, 40:11:764–774, 

1995. 

13. Richwald, G. A. et al., 

‘‘Effectiveness of the Cavity-Rim 

Cervical Cap: Results of a Large Clinical 

Study,’’ Obstetrics and Gynecology, 

74:2:143–148, 1989. 

14. Bernstein, G., ‘‘Use-Effectiveness 

Study of Cervical Caps: Final Report,’’

Washington, DC: National Institute of 

Child Health and Human Development, 

contract no. NO1–HD–1–2804, 1986. 

15. Gross, M. et al., ‘‘Rectal 

Microbicides for U.S. Gay Men. Are 

Clinical Trials Needed?,’’ Sexually 

Transmitted Diseases, 25:6:296–302, 

1998. 

16. Mansergh, G. et al., ‘‘Rectal Use of 

Nonoxynol–9 Among Men Who Have 

Sex With Men,’’ AIDS, 17:6:905–909, 

2003. 

17. Phillips, D. M. and V. R. 

Zacharopoulos, ‘‘Nonoxynol–9 

Enhances Rectal Infection by Herpes 

Simples Virus in Mice,’’ Contraception, 

57:341–348, 1998. 

18. Patton, D. et al., ‘‘Rectal 

Applications of Nonoxynol–9 Cause 

Tissue Disruption in a Monkey Model,’’

Sexually Transmitted Diseases, 29:581–

587, 2002. 

19. Phillips, D. et al., ‘‘Nonoxynol–9 

Causes Rapid Exfoliation of Sheets of 

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Federal Register / Vol. 72, No. 243 / Wednesday, December 19, 2007 / Rules and Regulations 71785 

Rectal Epithelium,’’ Contraception, 

62:149–154, 2002. 

20. Phillips, D. M. et al., ‘‘Lubricants 

Containing N–9 May Enhance Rectal 

Transmission of HIV and Other STIs,’’

Contraception, 70:107–110, 2004. 

List of Subjects in 21 CFR Part 201 

Drugs, Labeling, Reporting and 

recordkeeping requirements. 

■ Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, 21 CFR part 201 is 

amended as follows: 

PART 201—LABELING 

■ 1. The authority citation for 21 CFR 

part 201 continues to read as follows: 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 358, 360, 360b, 360gg–360ss, 371, 

374, 379e; 42 U.S.C. 216, 241, 262, 264. 

■ 2. Section 201.66 is amended by 

adding paragraph (c)(5)(ii)(H) to read as 

follows: 

§ 201.66 Format and content requirements 

for over-the-counter (OTC) drug product 

labeling. 

* * * * * 

(c) * * * 

(5) * * * 

(ii) * * * 

(H) Sexually transmitted diseases 

(STDs) warning for vaginal 

contraceptive and spermicide drug 

products containing nonoxynol 9 set 

forth in § 201.325(b)(2). This warning 

shall follow the subheading ‘‘Sexually 

transmitted diseases (STDs) alert:’’

* * * * * 

■ 3. Section 201.325 is added to subpart 

G to read as follows: 

§ 201.325 Over-the-counter drugs for 

vaginal contraceptive and spermicide use 

containing nonoxynol 9 as the active 

ingredient; required warnings and labeling 

information. 

(a) Studies indicate that use of vaginal 

contraceptive drug products containing 

nonoxynol 9 does not protect against 

infection from the human 

immunodeficiency virus (HIV), the virus 

that causes acquired immunodeficiency 

syndrome (AIDS), or against the 

transmission of other sexually 

transmitted diseases (STDs). Studies 

also indicate that use of vaginal 

contraceptive drug products containing 

nonoxynol 9 can increase vaginal 

irritation, such as the disruption of the 

vaginal epithelium, and also can cause 

epithelial disruption when used in the 

rectum. These effects may increase the 

risk of transmission of the AIDS virus 

(HIV) from an infected partner. 

Therefore, consumers should be warned 

that these products do not protect 

against the transmission of the AIDS 

virus (HIV) or other STDs, that use of 

these products can increase vaginal and 

rectal irritation, which may increase the 

risk of getting the AIDS virus (HIV) from 

an HIV infected partner, and that the 

products are not for rectal use. 

Consumers should also be warned that 

these products should not be used by 

persons who have HIV/AIDS or are at 

high risk for HIV/AIDS. 

(b) The labeling of OTC vaginal 

contraceptive and spermicide drug 

products containing nonoxynol 9 as the 

active ingredient, whether subject to the 

ongoing OTC drug review or an 

approved drug application, must 

contain the following warnings under 

the heading ‘‘Warnings,’’ in accordance 

with 21 CFR 201.66. 

(1) ‘‘[bullet] For vaginal use only 

[bullet] Not for rectal (anal) use’’ [both 

warnings in bold type]. 

(2) ‘‘Sexually transmitted diseases 

(STDs) alert [in bold type]: This product 

does not [word ‘‘not’’ in bold type] 

protect against HIV/AIDS or other STDs 

and may increase the risk of getting HIV 

from an infected partner’’. 

(3) ‘‘Do not use’’ [in bold type] if you 

or your sex partner has HIV/AIDS. If 

you do not know if you or your sex 

partner is infected, choose another form 

of birth control’’. 

(4) ‘‘When using this product [in bold 

type] [optional, bullet] you may get 

vaginal irritation (burning, itching, or a 

rash)’’. 

(5) ‘‘Stop use and ask a doctor if [in 

bold type] [optional, bullet] you or your 

partner get burning, itching, a rash, or 

other irritation of the vagina or penis’’. 

(c) The labeling of this product states 

under the ‘‘Other information’’ section 

of the Drug Facts labeling in accordance 

with § 201.66(c)(7), ‘‘[bullet] when used 

correctly every time you have sex, latex 

condoms greatly reduce, but do not 

eliminate, the risk of catching or 

spreading HIV, the virus that causes 

AIDS. 

(d) The labeling of this product 

includes the following statements either 

on the outside container or wrapper of 

the retail package, under the ‘‘Other 

information’’ section of the Drug Facts 

labeling in accordance with 

§ 201.66(c)(7), or in a package insert: 

(1) ‘‘[bullet] studies have raised safety 

concerns that products containing the 

spermicide nonoxynol 9 can irritate the 

vagina and rectum. Sometimes this 

irritation has no symptoms. This 

irritation may increase the risk of getting 

HIV/AIDS from an infected partner’’. 

(2) ‘‘[bullet] you can use nonoxynol 9 

for birth control with or without a 

diaphragm or condom if you have sex 

with only one partner who is not 

infected with HIV and who has no other 

sexual partners or HIV risk factors’’. 

(3) ‘‘[bullet] use a latex condom 

without nonoxynol 9 if you or your sex 

partner has HIV/AIDS, multiple sex 

partners, or other HIV risk factors’’. 

(4) ‘‘[bullet] ask a health professional 

if you have questions about your best 

birth control and STD prevention 

methods’’. 

(e) Any drug product subject to this 

section that is not labeled as required 

and that is initially introduced or 

initially delivered for introduction into 

interstate commerce after June 19, 2008, 

is misbranded under section 502 of the 

Federal Food, Drug, and Cosmetic Act 

(the act) (21 U.S.C. 352), is a new drug 

under section 505 of the act (21 U.S.C. 

355), and is subject to regulatory action. 

Dated: December 10, 2007. 

Jeffrey Shuren, 

Assistant Commissioner for Policy. 

[FR Doc. 07–6111 Filed 12–18–07; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF STATE 

22 CFR Part 124 

[Public Notice 6031] 

Amendment to the International Traffic 

in Arms Regulations: Regarding Dual 

and Third Country Nationals 

AGENCY: Department of State. 

ACTION: Final rule. 

SUMMARY: The Department of State is 

amending the text of the International 

Traffic in Arms Regulations (ITAR) to 

allow access to defense articles and 

services for dual and third country 

nationals of certain countries through 

revisions in procedures for technical 

assistance agreements and 

manufacturing licensing agreements. 

This regulatory change will reduce the 

burden on exporters of defense articles 

and on foreign parties to the agreements 

by reducing the number of individual 

Non Disclosure Agreements (NDA’s) 

which must be executed and maintained 

on file. 

DATES: Effective Date: This rule is 

effective December 19, 2007. 

ADDRESSES: Interested parties may 

submit comments at any time by any of 

the following methods: 

• E-mail: 

DDTCResponseTeam@state.gov with an 

appropriate subject line. 

• Mail: Department of State, 

Directorate of Defense Trade Controls, 

Office of Defense Trade Controls Policy, 

ATTN: Regulatory change, ITAR 

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