[Federal Register Volume 72, Number 243 (Wednesday, December 19, 2007)]
[Rules and Regulations]
[Pages 71769-71785]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 07-6111]


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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.

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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

[[Page 71770]]

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
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           Proposed Rule                          Final Rule
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``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.
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``Sexually transmitted diseases      ``Sexually transmitted diseases
 (STDs) alert: This product does      (STDs) alert:
 not protect against the AIDS virus  This product does not protect
 (HIV) or other STDs''                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.
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``Ask a doctor before use if you     ``Do not use if you or your sex
 have                                 partner has HIV/AIDS. If you do
<bullet> a new sex partner,           not know if you or your sex
 multiple sex partners, or            partner is infected, choose
 unprotected sex. Frequent use        another form of birth control.''
 (more than once a day) of this      ``When using this product you may
 product can increase vaginal         get vaginal irritation (burning,
 irritation, which may increase the   itching, or a rash)''
 risk of getting the AIDS virus       We discuss these changes in
 (HIV) or other STDs from infected    sections II.B.2, comment 3 and
 partners. Ask a doctor or other      II.C, comment 5 of this document.
 health professional for your best
 birth control method.''
------------------------------------------------------------------------

[[Page 71771]]

 
<bullet> ``Studies have raised       <bullet> ``studies have raised
 safety concerns that frequent use    safety concerns that products
 (more than once a day) of products   containing the spermicide
 containing nonoxynol 9 can           nonoxynol 9 can irritate the
 increase vaginal irritation, which   vagina and rectum. Sometimes this
 may increase the risk of getting     irritation has no symptoms. This
 the AIDS virus (HIV) or other STDs   irritation may increase the risk
 from infected partners. Vaginal      of getting HIV/AIDS from an
 irritation may include symptoms      infected partner''
 such as burning, itching, or a      We discuss this change in section
 rash, or you may not notice any      II.B.2, comment 3 of this
 symptoms at all. If you use these    document.
 products frequently and/or have a   <bullet> ``you can use nonoxynol 9
 new sex partner, multiple sex        for birth control with or without
 partners or unprotected sex, see a   a diaphragm or condom if you have
 doctor or other health               sex with only one partner who is
 professional for your best birth     not infected with HIV and who has
 control and methods to prevent       no other sexual partners or HIV
 STDs.''                              risk factors''.
                                     We discuss this change in sections
                                      II.F.3, comment 10 and II.G,
                                      comment 11 of this document.
                                     <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''.
                                     We discuss this change in section
                                      II.F.2, comment 9 of this
                                      document.
                                     <bullet> ``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.
------------------------------------------------------------------------
                                     <bullet> ``when used correctly
<bullet> ``correct use of a latex     every time you have sex, latex
 condom with every sexual act will    condoms greatly reduce, but do not
 help reduce the risk of getting      eliminate, the risk of catching or
 the AIDS virus (HIV) and other       spreading HIV, the virus that
 STDs from infected partners''.       causes AIDS.
                                     We discuss this change in section
                                      II.F.1, comment 8 of this
                                      document.
------------------------------------------------------------------------
Use of N9 products may increase the  Use of N9 products is associated
 risk of HIV and other STDs.          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:
    <bullet> N9 does not protect against HIV or STDs.
    <bullet> N9 causes damage to the vaginal lining and increases the 
risk of contracting HIV due to this vaginal irritation.
    <bullet> Many new cases of HIV and STDs will develop if 
contraceptives with N9 are available without consultation with a health 
professional.
    <bullet> 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:
    <bullet> N9 products are effective in preventing pregnancy, 
particularly when used with a barrier method such as a condom or 
diaphragm.
    <bullet> N9 products are a contraceptive option for women who 
cannot tolerate hormone-based birth control methods.
    <bullet> N9 products are a contraceptive option for women at low 
risk for HIV and STDs.
    <bullet> N9 products represent one of the few methods available for 
women that are controlled by women.
    <bullet> 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):

[[Page 71772]]

    <bullet> 16 for the diaphragm with spermicide.
    <bullet> 16 to 32 (depending on whether the women have had prior 
births) for the cervical cap with spermicide.
    <bullet> 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 self-medicating 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 self-medicating 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:
    <bullet> Twenty percent of the study subjects were lost to followup 
(so the investigators never determined the HIV status of these 
participants).
    <bullet> The results between the two test groups (N9 and placebo) 
were ``barely'' significant (p=0.047).
    <bullet> The placebo may have had a protective effect.
    <bullet> 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:
    <bullet> 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

[[Page 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.
    <bullet> The comparator product was changed midstream, indicating 
design problems.
    <bullet> More women had preexisting genital ulcers in the N9 test 
group, indicating randomization problems.
    <bullet> 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:
    <bullet> ``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.''
    <bullet> ``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:
    <bullet> ``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.''
    <bullet> ``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

[[Page 71774]]

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 dose-dependent 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:
    <bullet> 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.
    <bullet> There was a higher loss to followup rate in the N9 group 
compared to the placebo group.
    <bullet> 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, multi-center 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 HIV-negative 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

[[Page 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 Sec.  201.325(b)(2) and (b)(3) of the proposed 
rule stated:
    <bullet> Sexually transmitted diseases (STDs) alert:
    This product does not protect against HIV/AIDS or other STDs
    <bullet<ls-thn-eq> Ask a doctor before use if you have
    <bullet> 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 Sec.  201.325(c)(1) (redesignated as Sec.  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:
    <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.''
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

[[Page 71776]]

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 Sec.  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 
Sec.  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 Sec.  
201.66(c)(7). We also proposed additional labeling information in Sec.  
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 Sec.  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 Sec.  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 Sec.  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 Sec.  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 Sec.  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.''

[[Page 71777]]

    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 Sec.  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 low-
risk 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.

[[Page 71778]]

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 Sec.  201.325(c)(1) (redesignated as Sec.  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 no-

[[Page 71779]]

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 self-administered. 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 Sec.  
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 Sec.  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.

[[Page 71780]]

    (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 Sec.  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 Sec.  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 Sec.  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

[[Page 71781]]

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 Sec.  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 Sec.  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 Sec.  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 Sec.  201.66(c)(7), or in a package 
insert. The only exception is the statement in Sec.  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:
    <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''.
    <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''.
    <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. [this information must 
appear on the outside container or wrapper labeling in the Drug Facts 
labeling under ``Other information''].
    <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''.
    <bullet> ``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 Sec.  201.66.
BILLING CODE 6111-01-S

[[Page 71782]]

[GRAPHIC] [TIFF OMITTED] TR19DE07.033

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 
Diphenhydramine-Containing Drug Products for Over-the-Counter 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

[[Page 71783]]

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 
1.164\1\ ($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 SKU\2\.
---------------------------------------------------------------------------

    \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.)
    \2\The 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.
---------------------------------------------------------------------------

    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 $327,280\4\.
---------------------------------------------------------------------------

    \3\In 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.
    \4\In the proposed rule this value was reported as $321,000, but 
should have been $281,200.
---------------------------------------------------------------------------

    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

[[Page 71784]]

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-the-Counter 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

[[Page 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.

0
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

0
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.

0
2. Section 201.66 is amended by adding paragraph (c)(5)(ii)(H) to read 
as follows:


Sec.  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 Sec.  201.325(b)(2). This warning shall follow the subheading 
``Sexually transmitted diseases (STDs) alert:''
* * * * *

0
3. Section 201.325 is added to subpart G to read as follows:


Sec.  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 
Sec.  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 Sec.  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