Vaginal Contraceptive N-9 Label Warnings Urged “As Soon As Possible” – FDA

Manufacturers of vaginal contraceptives containing nonoxynol-9 should voluntarily implement proposed label warnings about increased vaginal irritation and HIV infection risk "as soon as possible," FDA advises in a ¹ Jan. 16 proposed rule.

"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 N-9 does not protect against the AIDS virus and that frequent use of N-9 can increase vaginal irritation," FDA says in the proposal.

However, immediate labeling changes would be "subject to the possibility that FDA may change the wording of the statements as a result of comments" submitted by April 16 in response to the proposed reg, the agency cautions.

FDA's proposed warning for N-9-containing vaginal contraceptives states: "Ask a doctor before use if you have a new sex partner, multiple sex partners or unprotected sex. Frequent use (more than once a day) of this product can increase vaginal irritation, which may increase the risk of becoming infected with the AIDS virus (HIV) or other STDs from infected partners."

The warning concludes: "Ask a doctor or other health professional for your best birth control method."

FDA also proposes labeling information, to be included either on the outside package or in a package insert, that conveys safety issues prompted by studies on the spermicide N-9.

In addition to noting studies have raised concerns that frequent use of N-9 can increase vaginal irritation and the risk of STDs, the warning states, in part: "Vaginal irritation may include symptoms such as burning, itching or a rash, or you may not notice any symptoms at all."

The agency also proposes the accompanying statement regarding condom use: "Correct use of a latex condom with every sexual act will help reduce the risk of getting the AIDS virus (HIV) and other STDs."

FDA further suggests labeling for N-9-containing vaginal contraceptives carry the heading "Sexually transmitted diseases (STDs) alert," followed by the statement: "This product does not protect against the AIDS virus or other sexually transmitted diseases."

FDA says it is "concerned with how well consumers understand the language in the proposed warnings and whether the proposed warnings convey the safety concerns for N-9 adequately." The agency invites comments on whether the proposed warnings are adequate and whether there are other data to "support, expand or refute the proposed warnings."

"Are there additional data to further clarify or specifically quantify the term 'frequent use' in the proposed warning," FDA asks. The agency also inquires whether the symp-toms of vaginal irritation are adequately defined, and whether additional data link an increase in vaginal irritation with increased risk of STD and HIV transmission.

The proposed rule cites numerous studies on N-9 conducted in Africa, Thailand, South America, Belgium, The Netherlands and the U.S. "Many of these studies suggest that N-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," the agency says.

"Several studies suggested a causal link between the frequency of use of N-9, increased vaginal irritation and the possibility that the vaginal irritation (such as the disruption of the vaginal epithelium) may increase the risk of transmission of the AIDS virus and other STDs," FDA says.

In May 2002, the Centers for Disease Control & Prevention advised against future purchases of condoms containing N-9 and against use of the spermicide alone in preventing HIV and STDs (² (Also see "N-9 Lubricated Condom Buys, Spermicide Use Discouraged In CDC Guidelines" - Pink Sheet, 13 May, 2002.), p. 4).

The proposed rule also references revised public health guidelines issued by the World Health Organization in June 2002. WHO concluded N-9 does not protect against HIV infection and may increase the risk of infection in women using the spermicide frequently (³ (Also see "N-9 Data Warrants Spermicide Safety Study, WHO Report Recommends" - Pink Sheet, 8 Jul, 2002.), p. 17).

Speaking at an international microbicides conference shortly after the CDC guidelines were released, an FDA medical officer said N-9 labeling modifications were under consideration by the agency but there were no plans to pull the spermicide off the market (⁴ (Also see "Nonoxynol-9 Labeling Changes Under Discussion At FDA" - Pink Sheet, 20 May, 2002.), p. 10).

In the proposed reg, FDA says the warnings and additional labeling information do not "require a finding that any or all of the OTC drug products that contain N-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."

The additional 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," the agency maintains.

There is no final monograph for OTC vaginal contraceptive products. Under a February 1995 tentative final monograph, manufacturers would be required to obtain approved NDAs or ANDAs for their products and to test them in clinical trials under actual use conditions (⁵ (Also see "OTC vaginal contraceptives TFM vacated; FDA asks for NDAs/ANDAs." - Pink Sheet, 6 Feb, 1995.), p. 2).

The TFM also encouraged manufacturers of vaginal contraceptives to evaluate use of the products in preventing STD transmission.

In the proposed rule, the agency observes that most OTC vaginal spermicides containing N-9 carry warnings to stop use and ask a doctor if irritation of the vagina or penis occurs.

Recommending a similar warning in the proposed rule, FDA says it "is not aware of any data that suggest increased penile irritation from frequent use of N-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."

FDA says it intends to consider the proposed labeling revisions, when finalized, as 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" 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."

FDA proposes a six-month effective date following publication of a final rule, recognizing that "implementation in a timeframe any less than six 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," FDA says.