[Federal Register Volume 68, Number 11 (Thursday, January 16, 2003)]
[Proposed Rules]
[Pages 2254-2262]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-902]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 80N-0280]
RIN 0910-AA01


Over-the-Counter Vaginal Contraceptive Drug Products Containing 
Nonoxynol 9; Required Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

SUMMARY: The Food and Drug Administration (FDA) is proposing new 
labeling warning statements for all over-the-counter (OTC) vaginal 
contraceptive drug products containing nonoxynol 9. These warning 
statements will advise consumers that vaginal contraceptives containing 
nonoxynol 9 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 will also advise consumers 
that frequent use of vaginal contraceptives containing nonoxynol 9 can 
increase vaginal irritation. Increased vaginal irritation from use of 
nonoxynol 9 may increase the possibility of transmission of the AIDS 
virus (HIV) and STDs from infected partners. The agency is requesting 
public comment on the proposed labeling statements and how such 
information could best be presented in labeling. This proposal is part 
of FDA's ongoing review of OTC drug products.

DATES: Submit written or electronic comments by April 16, 2003. Submit 
written or electronic comments on the agency's economic impact 
determination by April 16, 2003. Please see section IX of this document 
for the effective date of any final rule that may publish based on this 
proposal.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Arlene Solbeck, Center for Drug

[[Page 2255]]

Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

    In the advance notice of proposed rulemaking (ANPRM) for OTC 
vaginal contraceptive drug products (45 FR 82014, December 12, 1980), 
the Advisory Review Panel on OTC Contraceptives and Other Vaginal Drug 
Products (the Panel) placed nonoxynol 9 in category I (safe and 
effective). However, the Panel concluded that the contraceptive 
effectiveness of active ingredients cannot be considered separately 
from the vehicle and recommended that FDA require in vitro testing to 
determine the spermicidal effectiveness of each final formulation 
before marketing. In the preamble to the Panel's report (45 FR 82014), 
the agency stated that in vitro testing alone is an inadequate measure 
of a vaginal contraceptive product's effectiveness in humans. The 
agency explained that clinical trials of each product or final 
formulation may be the only certain predictor of its effectiveness in 
humans. The agency added that if clinical trials are necessary, 
manufacturers may be required to submit a new drug application (NDA) or 
supplement an existing NDA.
    In the notice of proposed rulemaking (NPRM) for OTC vaginal 
contraceptive drug products (60 FR 6892, February 3, 1995), the agency 
proposed that manufacturers of OTC vaginal contraceptive drug products 
obtain approved NDAs for marketing of their products. The agency 
proposed this action because effectiveness of these products is 
dependent upon the final formulation. Therefore, the agency proposed 
that each product be tested in appropriate clinical trials under actual 
conditions of use.
    In response to the NPRM, the agency is aware of ongoing clinical 
trials of vaginal contraceptives containing nonoxynol 9 (Refs. 1, 2, 
and 3). Pending the completion and analysis of these clinical trials, 
the agency is allowing the continued marketing of these products under 
the ongoing OTC drug review. These issues were discussed at the 
November 22, 1996, Nonprescription Drugs Advisory Committee (NDAC) 
meeting. NDAC concurred with the agency to allow interim marketing of 
nonoxynol 9 containing vaginal spermicides pending results from the 
proposed trials (Ref. 1). However, based on the studies discussed in 
section I of this document, the agency believes that vaginal 
contraceptive drug products containing nonoxynol 9 need to be labeled 
to inform users of these products that nonoxynol 9 does not prevent the 
transmission of the AIDS virus (HIV) and other STDs. Furthermore, users 
should be informed that frequent use of nonoxynol 9 can cause vaginal 
irritation and possibly increase the risk of becoming infected with the 
AIDS virus (HIV) and other STDs from infected partners. This rulemaking 
addresses certain safety concerns with the use of nonoxynol 9.
    Nonoxynol 9 is a nonionic surfactant that works as a vaginal 
contraceptive by damaging the cell membrane of sperm. It has been shown 
in certain in vitro studies to damage the cell wall of certain STD 
pathogens and to have activity against certain bacterial and viral STD 
pathogens, including HIV. However, based on the in vivo data described 
in section I of this document, the agency believes that this same cell 
membrane damaging effect can damage the vaginal and cervical epithelium 
(cell lining). Thus, nonoxynol 9 can have a negative impact on the 
vaginal lining and may increase the user's risk of getting STD/HIV and 
other genital infections. Irritation includes the range of physical 
findings from mild inflammation to epithelial disruption (damage to 
cells lining the vagina or cervix). Vaginal irritation may be 
symptomatic (with symptoms such as itching and burning) to asymptomatic 
(no symptoms).
    Because nonoxynol 9 kills the AIDS virus (HIV) and other STD 
pathogens in vitro, it has been suggested, over the years, that the 
drug might help prevent or reduce the risk of transmission of the AIDS 
virus and other STDs in humans. Information currently available to the 
general public creates the misperception that nonoxynol 9 might help 
decrease the risk of becoming infected with the AIDS virus and other 
STDs (Refs. 4 through 7). Thus, the agency believes that this proposed 
rule is necessary to provide a clear, consistent message that nonoxynol 
9 is not only ineffective in preventing HIV transmission, but that it 
could facilitate transmission of the disease.
    At the International AIDS Conference (July 9-14, 2000), researchers 
from the Joint United Nations Programme on AIDS (UNAIDS) presented the 
preliminary findings of a 4-year study conducted in a very high-risk 
population of 991 HIV negative female sex workers in Africa and 
Thailand to determine the effectiveness of a nonoxynol 9 gel (versus 
placebo) in preventing the transmission of HIV and STDs (Ref. 8). The 
test product contained 52.5 milligrams (mg) of nonoxynol 9 and a 
polymer with bioadhesive properties. The placebo contained only the 
polymer. Participants could be enrolled in the study if they did not 
use intravenous drugs or intravaginal spermicides other than the study 
drug. The participants reported an average of 3.6 partners per day and 
about 70 coital acts per month during the study. Condom use was 
encouraged. The preliminary study findings showed that women who used 
nonoxynol 9 gel had a higher incidence of new HIV infections (59) than 
those who used the placebo gel (41). Further, the more frequently women 
used only the nonoxynol 9 gel (without a condom to protect themselves), 
the higher their risk of becoming infected. Researchers also found that 
women who used nonoxynol 9 had more vaginal lesions, which might have 
facilitated the HIV transmission. Based on these preliminary study 
findings, on August 4, 2000, the Centers for Disease Control and 
Prevention (CDC) issued a letter (Ref. 9) stating ``given that N-9 
[nonoxynol 9] has now been proven ineffective against HIV transmission, 
the possibility of risk, with no benefit, indicates that N-9 should not 
be recommended as an effective means of HIV prevention.'' The final 
results of this study were recently published (Ref. 10) and 
substantiate the preliminary findings. The investigators stated that 
their data support the following conclusions: (1) Nonoxynol 9 increased 
the risk of HIV infection compared to placebo; (2) nonoxynol 9 had an 
adverse effect on vaginal epithelium when used frequently, thus 
increasing women's susceptibility to HIV; and (3) at low frequency use, 
nonoxynol 9 had no effect, either positive or negative, on HIV 
infection.
    Earlier studies (Refs. 11 through 14) suggested that nonoxynol 9 
vaginal spermicides may reduce gonococcal and chlamydial cervical 
infection and may even reduce the incidence of HIV infection. However, 
most of these studies did not assess the risk of acquiring HIV and the 
investigators stressed the need for more definitive randomized clinical 
trials. More recently, the International AIDS Conference report and the 
CDC letter (Refs. 8 and 9) have raised concerns that frequent use of 
nonoxynol 9 can increase vaginal and genital irritation and increase 
the risk of HIV transmission. Based on these safety concerns, the 
agency has reviewed studies on nonoxynol 9 conducted in Africa, 
Thailand, South America, Belgium, the Netherlands, and the United 
States that address the toxicity of

[[Page 2256]]

the vaginal use of nonoxynol 9 in relation to dose, frequency of use, 
and the risk of becoming infected with STD/HIV.
    Amaral et al. (Ref. 15) studied nonoxynol 9 in 18 women who were 
randomly and blindly assigned to an acid-buffering bioadhesive gel 
containing either 0 percent, 2.5 percent (125 mg), or 5 percent (250 
mg) nonoxynol 9. Exclusion factors included a history of STD in the 
last 12 months, using any vaginal product within 7 days before 
admission to the study, or a known allergy to nonoxynol 9. Subjects 
were asked to abstain from sexual intercourse 48 hours before admission 
and during the study and not to use any other intravaginal products 
during the study. One dose of the assigned gel was administered 
vaginally daily for 6 days. No irritation or symptoms were reported by 
users of the acid-buffering bioadhesive gel without nonoxynol 9. 
Erythema in the vulva, cervix, and vagina was noted in all subjects 
using the acid-buffering vehicle containing nonoxynol 9 (2.5 percent 
and 5 percent). No signs of de-epithelialization or ulcers were seen in 
any of the subjects. However, the authors concluded that the acid-
buffering vehicle did not protect the cervix, vagina, and vulva from 
the irritation caused by nonoxynol 9.
    Stafford et al. (Ref. 16) studied the effects of daily use for 7 
days of a nonoxynol 9 (100 mg) containing gel versus placebo gel in 40 
women who were not currently using any intravaginal products, did not 
have a current STD, had no history of genital ulcerative disease, and 
were not known to be HIV seropositive. The subjects were asked to avoid 
sexual intercourse during the treatment period. The nonoxynol 9 group 
had increased symptoms of irritation. Colposcopic (use of a magnifying 
instrument) and histologic (microscopic) examination of vaginal and 
cervical tissue showed evidence of inflammation in the genital tract. 
Also, a temporary reduction in the number of lactobacilli (bacteria 
found in the normal vaginal flora that appear to offer protective 
effects against the overgrowth of certain organisms that cause 
infection) was seen more frequently in the women using the nonoxynol 9 
gel.
    Rosenstein et al. (Ref. 17) studied the effect on normal vaginal 
flora of three intravaginal microbicides (dextrin sulfate, nonoxynol 9, 
or docusate sodium, in a gel dosage form) in three separate placebo-
controlled studies. In these studies, women using dextrin sulfate gel 
were asked to insert 5 milliliters of the gel intravaginally for 4 
consecutive nights and women using nonoxynol 9 gel and docusate sodium 
gel were asked to insert the respective gels for 7 consecutive nights. 
A reduction of lactobacilli occurred in 56 percent of women who used 
nonoxynol 9 and 63 percent of women who used docusate sodium. Women 
using nonoxynol 9 were also significantly more likely to become 
colonized abnormally than those using placebo. It appeared that women 
were more likely to have their vaginal flora return to normal after 
nonoxynol 9 treatment if the lactobacilli had not been depleted. The 
authors expressed concern that continuous use of nonoxynol 9 would 
cause the vaginal flora to be altered persistently and, together with 
an increased risk of vaginal mucosal inflammation, could induce 
susceptibility to urinary and gynecological infection. The authors 
noted that it was essential that potential microbicides be examined for 
activity against normal vaginal flora.
    In a single-blind crossover study of 33 women, Poindexter et al. 
(Ref. 18) compared three OTC vaginal spermicide formulations containing 
nonoxynol 9: A polycarbophil-based gel with 50 mg of nonoxynol 9, a 
cellulose-based gel with 100 mg of nonoxynol 9, and a polyurethane 
sponge with 1,000 mg of nonoxynol 9. The subjects refrained from coitus 
for 3 days prior to and during the 7 consecutive days of the treatment 
period. There was a 21-day washout period between each treatment. New 
gynecological abnormalities occurred in all three groups using 
nonoxynol 9. Abnormalities observed included redness, white epithelium, 
ulceration, mosaic petechiae, and squamous metaplasia. Redness was the 
most common abnormality. Ulceration was noted in 2 of the 31 users of 
the nonoxynol 9 cellulose-based gel formulation. The authors noted that 
the abnormal effects of the vaginal spermicides were more profound on 
the cervical mucosa than the vulvo-vaginal mucosa.
    Coggins et al. (Ref. 19) studied the safety of three vaginal 
spermicides containing nonoxynol 9: Film (70 mg), suppositories (150 
mg), and gel (200 mg). Each woman used each product for a 4-week period 
and reported to the study center every 2 weeks. The authors did not 
indicate if there was a washout period between treatments. To avoid the 
potential for irritation from frequent use of nonoxynol 9 containing 
products, only women whose average coital frequency was one or fewer 
acts of intercourse per day were eligible to be enrolled. In this 
study, no ulcers or genital lesions were detected and clinical signs of 
irritation were fairly uncommon and not frequent when compared to 
baseline. The authors concluded that these products are safe for low 
frequency use.
    Watts et al. (Ref. 20) evaluated the effects of nonoxynol 9 on the 
vaginal flora and epithelium of 48 women (16 in each group) after 
application of a single dose and in the absence of sexual intercourse. 
Quantitative vaginal cultures and colposcopy were done at baseline and 
at 0.5, 4, 24, 48, and 72 hours after insertion of one of three 
commercially available vaginal spermicides containing nonoxynol 9 (200-
mg gel, 52.5-mg gel, or 70-mg film). Symptoms and colposcopic 
abnormalities were rare after use of nonoxynol 9. The proportion of 
women with Escherichia coli (E. coli) increased with the gel containing 
200 mg of nonoxynol 9 per dose and the concentration of E. coli 
increased with all of the test products. The authors noted that the 
transient decreased concentration of lactobacilli and increased levels 
of E. coli seen with all three test products are of concern and likely 
are intensified and perpetuated with repeated use of nonoxynol 9 as a 
microbicide. The authors suggested that adverse effects may be enhanced 
with frequent or chronic use and that chronic use may cause changes in 
the vaginal flora that may lead to urinary tract infection and other 
resultant complications.
    Niruthisard et al. (Ref. 21) conducted a double-blind, local 
toxicity study on the effects of frequent use of nonoxynol 9 in 20 
women who were not considered to be at high risk for STDs. Fifteen 
women used 150-mg nonoxynol 9 containing suppositories and 5 women used 
placebos (lubricating suppositories) inserted vaginally hourly for 4 
consecutive hours each day for 14 consecutive days. The study concluded 
that none of the women who used the placebo suppositories had abnormal 
physical findings. Six women who used the nonoxynol 9 suppositories had 
physical findings, including epithelial disruption and/or bleeding. In 
four women, the break in the cervical epithelium appeared to be the 
result of the sloughing of a thin layer of cells. One woman had 
bleeding and sloughing of her vaginal mucosa and another had a severe 
reaction on her cervix that was bleeding and edematous. All of these 
adverse events resolved within 1 week of stopping nonoxynol 9 use. The 
authors cautioned that this pilot study should be confirmed by other 
trials and that these findings may not be extrapolated to other 
situations of nonoxynol 9 use.

[[Page 2257]]

    Roddy et al. (Ref. 22) followed up with a study in 175 women to 
evaluate effects of dosing on vaginal and cervical irritation using a 
vaginal suppository with 150 mg of nonoxynol 9 at various dosing 
frequencies for 2 weeks. The women agreed to refrain from sexual 
intercourse and douching during the study period. Clinical signs of 
genital irritation included erythema and epithelial disruption. 
Erythema in the vagina was the major clinical sign noted. Epithelial 
disruption was defined as a break in the epithelium lining of the 
vulva, vagina, or cervix. Women with vulvar irritation also had vaginal 
and cervical irritation. The symptoms that were attributed to genital 
irritation included dysuria, genital itching, and burning. The 
irritation from using nonoxynol 9 every other day was no different than 
using the placebo. Use of nonoxynol 9 once or twice a day increased the 
rate of epithelial disruption. Use of nonoxynol 9 four times a day 
increased the rate of epithelial disruption about five times that of 
the placebo. However, the authors noted that having symptoms was not 
predictive of clinical signs and women with obvious clinical signs did 
not always report symptoms. The authors stated that there is no 
conclusive evidence of a dose response, but the data suggest a stepwise 
increase in signs of irritation with an increasing number of doses per 
day.
    Van Damme et al. (Ref. 23) conducted a multicenter, randomized, 
double-blind, controlled trial with three groups (52.5-mg nonoxynol 9 
gel, placebo gel, and a no-treatment control), examining the use of a 
lower dose of nonoxynol 9 in 534 women at low risk of HIV infection. 
The subjects were healthy women with no evidence of STDs and no 
clinical or colposcopic abnormalities. The subjects were to apply the 
study products once daily at the same time each day for 14 days and 
were allowed to have sexual intercourse. Incidences of genital symptoms 
such as vaginal discharge, erythema, lesions, and petechial hemorrhage 
(the most frequent abnormality reported) were significantly greater in 
the group using the nonoxynol 9 gel than the other groups. Women in the 
group using the nonoxynol 9 gel were significantly more likely to 
develop a lesion than those in either the placebo or no-treatment 
group. The authors noted that the clinical significance is unclear with 
regard to the excess incidence of petechial hemorrhage in the nonoxynol 
9 group and of other types of lesions that were not associated with 
epithelial disruption. The authors stated that, in theory, it is 
possible that any type of genital lesion may increase a woman's risk of 
becoming infected with HIV, especially if it serves as a focus for the 
recruitment of HIV-infectable inflammatory cells. However, they stated 
that whether this is of significance will need to be ascertained by 
large-scale intervention trials in populations at high risk of HIV 
infection.
    The incidence of ulceration, abrasion, and STD or other genital 
infections was low for all three treatment groups. The authors 
suggested that these findings were the result of the once a day 
application of the nonoxynol 9 and that at this frequency of use the 
nonoxynol 9 gel can be considered safe. The authors also stated that 
having established the safety of a single application, it was important 
to evaluate the effects of multiple doses. They noted that a study, 
which was not cited, involving the application of the same nonoxynol 9 
gel four times daily had recently been completed.
    Kreiss et al. (Ref. 24) studied 138 HIV seronegative female sex 
workers at very high risk of HIV seroconversion who were randomly 
assigned to a nonoxynol 9 (1,000 mg) containing vaginal sponge or 
placebo (glycerin vaginal suppository containing mineral oil, 
subsequently a water-based vaginal cream was used). Subjects were 
instructed to insert a sponge before the first sex partner each day, 
replace the sponge after every two to three partners, and remove the 
sponge 6 hours after the last sex partner. All subjects were 
intensively counseled and urged to have each sexual partner use 
condoms. Women in the study used the sponge an average of 14 times per 
week. Women were asked to return for followup at monthly intervals or 
more frequently if needed. The duration range for followups was between 
1 and 46 months. The mean (average) duration period of followup was 14 
months for the nonoxynol 9 group and 17 months for the placebo group. 
Spermicide-attributed complaints, mostly vulvar irritation, burning, 
and ulceration, were reported in 47 percent of the nonoxynol 9 users 
and 7 percent of the placebo users. There was a higher seroconversion 
(i.e., testing showing conversion from HIV negative to HIV positive) in 
women using the nonoxynol 9 containing sponge than the placebo product. 
Because of concern regarding the adverse local effects of the nonoxynol 
9 (1,000 mg) containing sponge, and its potential for increasing the 
risk of HIV transmission, rather than being protective, the study was 
prematurely terminated.
    Martin et al. (Ref. 25) studied the use of a nonoxynol 9 gel (52.5 
mg) in 52 HIV seronegative female sex workers. Subjects had to be free 
of STDs and any evidence of genital epithelial disruption, and had to 
report 100 percent compliance with condom use. Subjects were randomized 
to the nonoxynol 9 gel or to a placebo group and used one applicatorful 
per day. After a 14-day washout period, the subjects used the other 
treatment for 14 days. Subjects were evaluated by a questionnaire and 
physical examinations, including colposcopy. The authors concluded that 
daily application of the 52.5-mg nonoxynol 9 gel was safe, but they 
made no extrapolations to more frequent use. However, the authors 
acknowledged the shortness of the duration of use and that the power of 
this study to detect a small increase in epithelial toxicity might be 
limited.
    Roddy et al. (Ref. 26) studied the use of a nonoxynol 9 containing 
film as a vaginal microbicide in 1,295 HIV-negative female sex workers. 
In a double-blind, placebo-controlled study, the subjects were 
instructed to have their male sexual partners use latex condoms and 
were randomly assigned to use either the nonoxynol 9 film or a placebo 
film. At monthly followup visits, the women were examined with a 
colposcope for genital lesions and were tested for gonorrhea, 
chlamydia, and HIV infection. Seventy-three percent of the women 
remained in the study for 12 months with a mean followup period of 
approximately 14 months. The authors concluded that the use of the 
nonoxynol 9 vaginal film did not reduce the rate of new HIV, gonorrhea, 
or chlamydia infection even in those that used latex condoms and who 
received treatment for STDs.
    Van Damme et al. (Ref. 27) looked at more frequent use of the 
nonoxynol 9 (52.5 mg) gel among 320 HIV-seronegative female sex workers 
who did not have clinical STDs, genital ulcers, or abrasions, did not 
use illicit drugs, and participated in a 100 percent condom-use 
program. The study was designed as a randomized, placebo-controlled, 
triple-blind trial to assess the effect of nonoxynol 9 gel in the 
prevention of HIV/STD infection. Subjects were instructed to apply the 
test product or the placebo (gel vehicle without the nonoxynol 9) and 
to have their male sexual partners use a condom for every sex act. 
There were major differences in condom use between the study centers. 
The mean number of applicators of the daily gel use was 1.2 and 1.3, 
respectively, in the treatment and placebo groups. Colposcopy

[[Page 2258]]

examinations showed that vaginal irritation, such as ulcerations, 
abrasions (on the cervix and external genitalia), lesions, and 
erythema, was observed in both the treatment and the placebo groups. 
However, based on the number and incidences of colposcopic lesions per 
followup period of up to 12 weeks, the incidence of colposcopic lesions 
was low and there was no difference between the treatment groups. The 
authors reported that in both groups the chance of having a lesion 
increased with an increase in the mean daily use of the product. The 
authors concluded that multiple daily use of the nonoxynol 9 containing 
gel did not show an increase of local toxicity over the placebo gel.
    Rustomjee et al. (Ref. 28) studied a vaginal contraceptive film 
containing 72 mg of nonoxynol 9 versus a glycerin placebo film in a 
randomized, double-blind, crossover trial. The 20 subjects were female 
sex workers, and HIV infection was not an exclusion criteria. Subjects 
used either the treatment film or placebo film for 1 month and, after a 
1-month film-free washout period, used the other film for the last 
month. Condoms were provided. The differences in signs and symptoms of 
genital lesions from use of the nonoxynol 9 film and the placebo film 
did not reach statistical significance. However, the authors cautioned 
that the clinical findings of an increase in minor erythematous genital 
lesions in the nonoxynol 9 group, together with an increased HIV viral 
load associated with the presence of a minor genital lesion, is 
worrisome.
    In summary, many of the studies (Refs. 8, 15 through 18, 20 through 
24, and 28) suggest that nonoxynol 9 vaginal contraceptive formulations 
can increase the chances of vaginal and genital tract irritation, and 
cause disruption of the vaginal epithelium or the vaginal flora. Some 
studies (Refs. 8, 20, 22, and 23) suggest the risk of these adverse 
events can be increased by frequent and/or chronic use. One study (Ref. 
25) concluded that once a day use was safe, but noted that the power to 
detect a small increase in epithelial toxicity may be limited by the 
short duration of use. Investigators in one study (Ref. 27) concluded 
that multiple daily use of nonoxynol 9 (52.5 mg) gel was safe, but in a 
previous study (Ref. 23) of nonoxynol 9 (52.5 mg) gel in women with low 
risk of HIV infection, the investigators concluded that women using 
nonoxynol 9 gel were significantly more likely to develop lesions than 
those in the placebo or no-treatment groups. The authors stated that 
large scale intervention trials were needed to determine if genital 
lesions increase the risk of acquiring HIV infection.
    Several studies suggested a causal link between the frequency of 
use of nonoxynol 9, increased vaginal irritation, and the possibility 
that vaginal irritation (such as the disruption of the vaginal 
epithelium) may increase the risk of transmission of the AIDS virus 
(HIV) and other STDs. The preliminary findings of a study on nonoxynol 
9 (52.5 mg) gel presented at the International AIDS Conference in July 
2000 (Ref. 8) suggested that nonoxynol 9 does not prevent the 
transmission of HIV and other STDs and may facilitate the transmission 
of these pathogens. Another study (Ref. 26) concluded that the use of a 
nonoxynol 9 containing film did not reduce the rate of new HIV, 
gonorrhea, or chlamydia infection even when latex condoms were used. 
Other studies (Refs. 20, 24, and 28) also suggested that the adverse 
effects of nonoxynol 9 on the vaginal flora and epithelium may increase 
the risk of transmission of the AIDS virus (HIV), certain other STDs, 
and/or genital infections. The studies in high risk populations (sex 
workers) (Refs. 8, 24, 25, 27, and 28) suggested the possibility that 
the frequency of use of nonoxynol 9 can increase vaginal irritation and 
epithelium disruption. Such increased irritation may increase the risk 
of becoming infected with STDs, including the AIDS virus (HIV) from 
infected partners.
    The CDC, on May 10, 2002, published a report containing a 
recommendation that women, particularly those at risk for HIV or STDs, 
be informed that nonoxynol 9 contraceptives do not protect against 
these infections (Ref. 29). The CDC report described the extent of 
nonoxynol 9 contraceptive use in women in 1999 and summarized recent 
publications on nonoxynol 9 and HIV/STDs. According to this report, 
most women in the United States with HIV become infected through sexual 
transmission. Thus, the report underscores the importance of alerting 
women about the safety concerns surrounding nonoxynol 9.
    On June 28, 2002, the World Health Organization (WHO) issued 
revised public health guidelines for the use of nonoxynol 9 for HIV and 
STD prevention and for pregnancy prevention in populations at high risk 
for HIV (Ref. 30). The guidelines were based on a review of current 
clinical safety and effectiveness data on nonoxynol 9 (Ref. 31). The 
WHO guidelines advised that ``Spermicides containing nonoxynol 9 do not 
protect against HIV infection and may even increase the risk of HIV 
infection in women using these products frequently.'' The guidelines 
also advised women at high risk of HIV infection against using 
nonoxynol 9 spermicides for contraception.
    Based on safety concerns, the agency considers it important to 
alert users of OTC vaginal contraceptives containing nonoxynol 9 that 
these products do not prevent transmission of the AIDS virus (HIV) and 
other STDs, and that frequent use of these products can increase 
vaginal irritation, which may increase the risk of getting certain 
STDs, including the AIDS virus (HIV) from infected partners. The agency 
also believes that product labeling should include a 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.
    FDA's proposal to require these warnings and other information does 
not require a finding that any or all of the OTC drug products that 
contain nonoxynol 9 actually caused an adverse event, and FDA does not 
so find. Nor does FDA's requirement of warnings and other information 
repudiate the OTC drug monographs under which the affected drug 
products have been lawfully marketed. Rather, as a consumer protection 
agency, FDA has determined that these additional warnings and other 
information 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. This judgment balances the benefits of 
these drug products against their potential risks, and reflects our 
conclusion that even a potential link between the use of nonoxynol 9 
and serious adverse health consequences warrants this action (see CFR 
330.10(a)).
    FDA's decision to act in an instance such as this one 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 a warning, or take similar regulatory action, 
FDA need not show, nor do we allege, actual causation.
    In the NPRM (60 FR 6892 at 6901), the agency stated that consumers 
should be warned about possible allergic reactions such as burning and 
itching of the vagina and penis that may occur when using vaginal 
contraceptive drug products. The agency recommended that the following 
warning be included in the labeling: ``If you or your partner develops 
irritation, such as burning or itching in the genital area, stop using 
this product. If irritation continues,

[[Page 2259]]

contact your physician.'' At the November 22, 1996, NDAC meeting (Ref. 
1), the committee also noted that penile irritation could occur. The 
agency is aware that the labeling of most OTC marketed vaginal 
spermicides containing nonoxynol 9 bears a warning to stop use and ask 
a doctor if irritation of the vagina or penis occurs or continues. In 
this document, the agency is proposing a similar warning. The agency is 
not aware of any data that suggest increased penile irritation from 
frequent use of nonoxynol 9 may increase the risk of getting STDs from 
infected female partners. However, the agency encourages more research 
and studies to evaluate this potential safety concern.

II. The Agency's Proposal

    The agency is proposing to amend part 201 (21 CFR part 201) by 
adding Sec.  201.325 entitled ``Over-the-counter drugs for vaginal 
contraceptive use containing nonoxynol 9 as the active ingredient; 
required warnings.'' This section would require new warnings for all 
OTC vaginal contraceptive drug products containing nonoxynol 9 as the 
active ingredient, whether marketed under an NDA or the ongoing OTC 
drug review. The agency is proposing to require the following warnings 
be added to the labeling of all marketed OTC vaginal contraceptives 
containing nonoxynol 9: ``Sexually transmitted diseases (STDs) alert 
[heading in bold type]: This product does not [this word highlighted in 
bold type] protect against the AIDS virus (HIV) or other sexually 
transmitted diseases (STDs).''
    Based on the studies, the agency is also proposing a warning to 
inform users of OTC vaginal spermicides containing nonoxynol 9 that 
frequent use can increase vaginal irritation and may increase the risk 
of getting the AIDS virus (HIV) or other STDs from infected partners. 
The statements would also quantify the definition of ``frequent use'' 
by adding ``(more than once a day)''. The proposed warning states:
    Ask a doctor before use if you have [heading in bold type] 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 agency is also proposing a warning to stop use and ask a doctor if 
irritation of the vagina or penis occurs. The agency recommended a 
similar warning in the NPRM (60 FR 6892 at 6901): ``If you or your 
partner develops irritation, such as burning or itching in the genital 
area, stop using this product. If irritation continues, contact your 
physician.'' The agency is revising that warning in this document to 
state: ``Stop use and ask a doctor if [heading in bold type] you or 
your partner get burning, itching, a rash, or other irritation of the 
vagina or penis.'' Further, the warning that reads ``For vaginal use 
only'' needs to be included in accordance with the requirements in 
Sec.  201.66(c)(5)(i).
    Because of the public health concerns regarding the transmission of 
STDs and the AIDS virus (HIV), the agency believes that manufacturers 
should inform consumers as soon as possible that nonoxynol 9 does not 
protect against the AIDS virus (HIV) and that frequent use of nonoxynol 
9 can increase vaginal irritation. FDA encourages manufacturers of all 
OTC vaginal contraceptive drug products containing nonoxynol 9 to 
implement the agency's proposed labeling warnings voluntarily as soon 
as possible, subject to the possibility that FDA may change the wording 
of the statements, as a result of comments submitted in response to 
this proposal. The agency considers these warnings important to the 
safe use of OTC vaginal contraceptive drug products containing 
nonoxynol 9.
    Because there is no final monograph for these products at present, 
manufacturers of OTC vaginal contraceptive drug products containing 
nonoxynol 9 are required to follow the labeling requirements in Sec.  
201.66 as of the first major labeling revision after May 16, 2002. The 
agency intends to consider the labeling revisions in this proposal, 
when finalized, to be the first major labeling revision after May 16, 
2002, for products that have not already converted to the ``Drug 
Facts'' labeling format, and to require those products to conform to 
Sec.  201.66 at that time. For products that have already converted to 
the ``Drug Facts'' format, the agency will require the labeling 
revisions in this proposal to be implemented by the effective date of 
the final rule.
    In addition, the agency is proposing to require additional labeling 
information which would convey to consumers that studies have raised 
safety concerns that increased vaginal irritation (i.e., irritation or 
damage to the cell lining of the vagina that may or may not produce 
symptoms) caused by frequent use of nonoxynol 9 may make one more 
susceptible to the risk of getting the AIDS virus (HIV) or other STDs 
from infected partners and that consumers who use these products 
frequently should seek further advice from a doctor or other health 
professional for their best birth control method. In the interest of 
public health, the information would also include a statement to 
encourage the use of a latex condom with every sexual act to help to 
reduce the risk of getting the AIDS virus (HIV) and other STDs. The 
agency is proposing that this labeling be included 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 or in a package insert. Many of the marketed OTC vaginal 
contraceptive 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 that package insert. The agency is proposing 
the following labeling:
    [sbull] 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.
    [sbull] Correct use of a latex condom with every sexual act will 
help reduce the risk of getting the AIDS virus (HIV) and other STDs.
    The studies suggest a possible correlation between increased 
vaginal irritation from frequent use and the risk of transmission of 
the AIDS virus (HIV) and other STDs. Because of this significant safety 
concern, the agency is asking for comments on how to best present this 
information in the product labeling.

III. Questions to be Addressed

    The agency is concerned with how well consumers understand the 
language in the proposed warnings and whether the proposed warnings 
convey the safety concerns for nonoxynol 9 adequately. The agency 
invites public comments on the following questions:
    1. Do the proposed warnings under the headings ``Sexually 
transmitted diseases alert,'' ``Ask a doctor before use if you have,'' 
and ``Stop use and ask a doctor if'' adequately convey the safety 
concerns to consumers? What revisions, if any, would be useful?
    2. Are there other data to support, expand, or refute the proposed 
warnings?
    3. Are there additional data to further clarify or specifically 
quantify the term ``frequent use'' in the proposed warning that states: 
``Frequent use (more than once a day) of this product can increase

[[Page 2260]]

vaginal irritation, which may increase the risk of getting the AIDS 
virus (HIV) or other STDs from infected partners''?
    4. Are the symptoms of vaginal irritation adequately defined? Are 
there other symptoms that should be included?
    5. Are there additional data to correlate an increase in vaginal 
irritation with an increased risk of transmission of HIV and other 
STDs? If so, how should such information be conveyed in labeling?
    6. Is a package insert the best way to provide additional 
information to consumers or should this information appear on the outer 
carton?
    7. Are the proposed statements for the package insert appropriate? 
What revisions or additional information, if any, would be useful to 
make the package insert more informative and consumer friendly?

IV. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1501 et seq.). 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). Under the Regulatory 
Flexibility Act, if a rule has a significant impact on a substantial 
number of small entities, an agency must analyze regulatory options 
that would minimize any significant impact of the rule on small 
entities. Section 202(a) of the Unfunded Mandates Reform Act of 1995 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure in any one year by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation).
    The agency believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
FDA has determined that the proposed rule is not a significant 
regulatory action as defined by the Executive order and so is not 
subject to review under the Executive order.
    The Unfunded Mandates Reform Act does not require FDA to prepare a 
statement of costs and benefits for this proposed rule, because the 
proposed rule is not expected to result in any 1-year expenditure that 
would exceed $100 million adjusted for inflation. The current inflation 
adjusted statutory threshold is about $110 million.
    The purpose of this proposed rule is to require additional labeling 
for OTC vaginal contraceptive drug products containing nonoxynol 9. 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. The agency is aware that most of the currently marketed 
products already include a consumer package insert. Therefore, to allow 
firms greater flexibility, the agency is allowing almost half 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 
proposed 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. The 
agency assumes the same weighted average cost to relabel (i.e., $3,600 
per stock keeping unit (SKU) (individual products, packages, and 
sizes)) that it estimated for the final rule requiring uniform label 
formats of OTC drug products (64 FR 13254 at 13279 to 13281, March 17, 
1999). Inventory loss was estimated using data from a study supporting 
the fore mentioned rule. With a 6-month implementation period, 
inventory loss was estimated to be between $500 and $3,000 per SKU, 
depending on product sales, for an estimated weighted average inventory 
loss of $2,050 . The inventory loss and redesign costs for the package 
insert are estimated to be about $1,380 per SKU.
    The agency's Drug Listing System identifies 15 manufacturers and 
distributors of OTC vaginal contraceptive drug products containing 
nonoxynol 9 that together produce approximately 40 SKUs. At a 
relabeling cost of $3,600 per SKU and an inventory loss of $2,050 per 
SKU, estimated total one-time costs of relabeling could be $266,000 (40 
x ($3,600 + $2,050)). 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 $55,200 (40 x 
$1,380) to the one-time cost, for an estimated total of $321,200.
    As the agency 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 
proposed rule does not require any new reporting or recordkeeping 
activities. No additional professional skills are needed.
    About 9 firms affected by this proposed 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 proposed rule. The average incremental cost 
per SKU to comply with this proposed rule is estimated to be $8,030 
($321,200/40 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. The agency 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.
    The agency has tentatively considered but rejected several labeling 
alternatives: (1) A shorter or longer implementation period, and (2) an 
exemption from coverage for small entities. The agency 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, 
the agency considers a period of 12 months too long to implement this 
new labeling. The agency rejected an exemption for small entities 
because the new labeling is also needed by consumers who purchase 
products marketed by those entities. Further, because of the importance 
of this information, the agency is not proposing a longer effective 
date for any products with annual sales less than $25,000.
    The analysis shows that this proposed rule is not economically 
significant under Executive Order 12866 and that the agency has 
considered the burden to small entities. Based on this analysis, the 
agency does not believe manufacturers will incur a significant

[[Page 2261]]

economic impact. Therefore, the agency certifies that the proposed 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)).
    The agency invites public comment regarding any substantial or 
significant economic impact that this proposed rule would have on 
companies marketing OTC vaginal contraceptive drug products containing 
nonoxynol 9. Types of impact may include, but are not limited to, costs 
associated with relabeling or repackaging. Comments regarding the 
impact of this proposed rule should be accompanied by appropriate 
documentation. The agency is providing a period of 90 days from the 
date of publication of this proposed rule in the Federal Register for 
comments on this subject to be developed and submitted. The agency will 
evaluate any comments and supporting data that are received and will 
reassess the economic impact of this proposed rule in the preamble to 
the final rule.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements proposed 
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 proposed 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

    The agency 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 proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
the agency tentatively concludes that the proposed rule does not 
contain policies that have federalism implications as defined in the 
Executive order and, consequently, a federalism summary impact 
statement has not been prepared.

VIII. Request for Comments

    Interested persons may submit written or electronic comments on the 
proposed rule, the agency's specific questions in section III of this 
document, and the agency's economic impact determination to the Dockets 
Management Branch (see ADDRESSES) by April 16, 2003. Three copies of 
all written comments are to be submitted. Individuals submitting 
written comments or anyone submitting electronic comments may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document and may be accompanied by a 
supporting memorandum or brief. Received comments may be seen in the 
Dockets Management Branch between 9 a.m. and 4 p.m., Monday through 
Friday.

IX. Proposed Effective Date

    Because of the importance of the proposed warnings to the safe use 
of OTC vaginal contraceptive drug products containing nonoxynol 9, the 
agency is proposing that any final rule that may publish based on this 
proposal become effective 6 months after its date of publication in the 
Federal Register.

X. References

    The following references are on display in the Dockets Management 
Branch (see ADDRESSES), under Docket No. 80N-0280, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. FDA, Transcript of Joint Meeting of the Nonprescription 
Drugs, Reproductive Health Drugs, Anti-Infective Drugs and Antiviral 
Drugs Advisory Committees, in OTC vol. 11ATFM3, November 22, 1996.
    2. Letter from D. L. Bowen, FDA, to R. W. Soller, 
Nonprescription Drug Manufacturers Association, coded LET 6.
    3. Letter from D. L. Bowen, FDA, to R. W. Soller, 
Nonprescription Drug Manufacturers Association, coded LET 7.
    4. Jim Shelton's Pearls for July 2000, ``Spermicides and 
Protection Against STDs,'' Johns Hopkins Center for Communication 
Programs, in OTC vol. 11ATFM3, 2000.
    5. Jim Shelton's Pearls for September 2000, ``Nonoxynol-9 and 
HIV Transmission,'' Johns Hopkins Center for Communication Programs, 
in OTC vol. 11ATFM3, 2000.
    6. University of Florida, ``HIV/AIDS Information/Resources.''
    7. Drugs.com (Drug Information Online), ``Spermicides Vaginal,'' 
in OTC vol. 11ATFM3.
    8. Van Damme, L., ``Advances in Topical Microbicides,'' 
presented at the XIII International AIDS Conference, Durban, South 
Africa, July 9-14, 2000.
    9. Letter from H. D. Gayle, National Center for HIV, STD, and TB 
Prevention, Centers for Disease Control and Prevention, in OTC vol. 
11ATFM3, August 4, 2000.
    10. Van Damme, L. et al, ``Effectiveness of COL-1492, a 
Nonoxynol-9 Vaginal Gel, on HIV-1 Transmission in Female Sex 
Workers: A Randomised Controlled Trial,'' The Lancet, 360:974-977, 
2002.
    11. Austin, H., W. C. Louv, and W. J. Alexander, ``A Case-
Control Study of Spermicides and Gonorrhea,'' Journal of the 
American Medical Association, 251:2822-2824, 1984.
    12. Rosenberg, M. J. et al., ``Effect of the Contraceptive 
Sponge on Chlamydial Infection, Gonorrhea, and Candidiasis,'' 
Journal of the American Medical Association, 257:2308-2313, 1987.
    13. Niruthisard, S., R. E. Roddy, and S. Chutivongse, ``Use of 
Nonoxynol-9 and Reduction in Rate of Gonococcal and Chlamydial 
Cervical Infections,'' The Lancet, 339:1371-1376, 1992.
    14. Zekeng, L. et al., ``Barrier Contraceptive Use and HIV 
Infection Among High Risk Women in Cameroon,'' AIDS, 7:725-731, 
1993.
    15. Amaral, E. et al., ``Study of the Vaginal Tolerance to 
Acidform, an Acid Buffering Gel,'' Contraception, 60(6):361-366, 
1999.
    16. Stafford, M. K. et al., ``Safety Study of Nonoxynol-9 as a 
Vaginal Microbicide; Evidence of Adverse Effects,'' Journal of 
Acquired Immune Deficiency Syndromes and Human Retrovirology, 
17:327-331, 1998.
    17. Rosenstein, I. J. et al., ``Effect on Normal Vaginal Flora 
of Three Intravaginal Microbicidal Agents Potentially Active Against 
Human Immunodeficiency Virus Type 1,'' The Journal of Infectious 
Diseases, 177:1386-1390, 1998.
    18. Poindexter III, A. N. et al., ``Comparison of Spermicides on 
Vulvar, Vaginal, and Cervical Mucosa,'' Contraception, 53:147-153, 
1996.
    19. Coggins, C. et al., ``Safety of Three Formulations of 
Nonoxynol-9 Containing Vaginal Spermicides,'' International Journal 
of Gynecology and Obstetrics, 68:267-268, 1999.
    20. Watts, H. et al., `` The Effects of Three Nonoxynol-9 
Preparations on Vaginal Flora and Epithelium,'' The Journal of 
Infectious Diseases, 180:426-437, 1999.
    21. Niruthisard, S., R. E. Roddy, and S. Chutivongse, ``The 
Effects of Frequent Nonoxynol-9 Use on the Vaginal and Cervical 
Mucosa,'' Journal of the American Venereal Disease Association, 
18:176-179, 1991.
    22. Roddy, R. E. et al., ``A Dosing Study of Nonoxynol-9 and 
Genital Irritation,'' International Journal of STD and AIDS, 4:165-
170, 1993.
    23. Van Damme, L. V. et al., ``Safety Evaluation of Nonoxynol-9 
Gel in Women at Low Risk of HIV Infection,'' AIDS, 12:433-437, 1998.
    24. 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.
    25. Martin, H. L. et al., ``Safety of a Nonoxynol-9 Vaginal Gel 
in Kenyan

[[Page 2262]]

Prostitutes,'' Sexually Transmitted Diseases, 24(5):279-283, 1997.
    26. 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.
    27. Van Damme, L. V. et al., ``Safety of Multiple Daily 
Applications of COL-1492, A Nonoxynol-9 Vaginal Gel, Among Female 
Sex Workers,'' AIDS 2000, 14(1):85-88, 2000.
    28. Rustomjee, R. et al., ``Phase 1 Trial of Nonoxynol 9 Film 
Among Sex Workers in South Africa,'' AIDS, 13:1511-1515, 1999.
    29. CDC, ``Nonoxynol-9 Spermicide Contraception Use--United 
States, 1999,'' Morbidity and Mortality Weekly Report, 51(18): 389-
392, 2002.
    30. WHO, ``Nonoxynol-9 Ineffective in Preventing HIV 
Infection,'' May 28, 2002.
    31. WHO, ``WHO/CONRAD Technical Consultation on Nonoxynol-9, 
Summary Report,'' 2001.

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 201 be amended as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360b, 
360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

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


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 drug products containing nonoxynol 9 set forth in Sec.  
201.325(b)(2). This warning shall follow the subheading ``Sexually 
transmitted diseases (STDs) alert:''

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


Sec.  201.325  Over-the-counter drugs for vaginal contraceptive use 
containing nonoxynol 9 as the active ingredient; required warnings.

    (a) Studies indicate that use of vaginal contraceptives 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 suggest that 
frequent use of vaginal contraceptives containing nonoxynol 9 can 
increase vaginal irritation, such as the disruption of the vaginal 
epithelium. These effects may increase the risk of transmission of the 
AIDS virus (HIV) and other STDs from an infected partner. Consumers 
should be warned that these products do not protect against the 
transmission of the AIDS virus (HIV) or other STDs. In addition, 
frequent use of these products can increase vaginal irritation, which 
may increase the risk of getting certain STDs, including the AIDS virus 
(HIV), from infected partners.
    (b) The labeling of OTC vaginal contraceptive 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 Sec.  201.66.
    (1) ``For vaginal use only'' [this heading in bold type]
    (2) ``Sexually transmitted diseases (STDs) alert [this heading in 
bold type]: This product does not [this word in bold type] protect 
against the AIDS virus (HIV) or other STDs.''
    (3) ``Ask a doctor before use if you have [heading in bold type] 
[optional, 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 getting 
the AIDS virus (HIV) or other STDs from infected partners. Ask a doctor 
or other health professional for your best birth control method.''
    (4) ``Stop use and ask a doctor if [heading 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 must include 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 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.''
    (2) ``[Bullet] 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.''
    (d) 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 [date 6 months after date 
of publication of the final rule in the Federal Register], 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 19, 2002.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 03-902 Filed 1-15-03; 8:45 am]
BILLING CODE 4160-01-S