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Division of Over-The-Counter Drug Products (HFD-560)

Center for Drug Evaluation and Research • Food and Drug Administration

Rockville • MD 20857

  ----------------------------------- --------------- -----------------------------------
  **CONDITIONS**                      0.2 to 0.5      
                                      percent and 0.3 
                                      to 1.0 percent  
                                      triclosan as an 
                                      active          
                                      ingredient in   
                                      leave-on and    
                                      rinse-off       
                                      dosage forms,   
                                      respectively,   
                                      of topical acne 
                                      drug products   

                                                      

  **PHARMACOLOGICAL CLASS**           Topical         
                                      Antimicrobial   
                                      Drug Products   

                                                      

  **MONOGRAPH**                                       Topical Acne Drug Products (21 CFR
                                                      Part 333, Subpart D)

                                                      

  **APPLICANT**                                       Ciba Specialty Chemicals
                                                      Corporation

                                                      4090 Premier Drive

                                                      P.O. Box 2444

                                                      High Point, NC 27265

                                                      

  **ORIGINAL TEA SUBMISSION DATE**                    December 17, 2004

                                                      

  **ORIGINAL TEA RECEIVED DATE**                      December 20, 2004

                                                      

  **ORIGINAL TEA REVIEW DATE**                        January 20, 2005

  **AMENDED TEA SUBMISSION DATE**                     April 22, 2005

                                                      

  **AMENDED TEA RECEIVED DATE**                       April 22, 2005

                                                      

  **AMENDED TEA REVIEW DATE**                         April 27, 2005

                                                      

  **REVIEWER**                                        Michael L. Koenig, Ph.D.

                                                      

  **TEAM LEADER**                                     Matthew R. Holman, Ph.D.
  ----------------------------------- --------------- -----------------------------------

**BACKGROUND**

The applicant requests addition of triclosan, 0.2 to 1.0 percent*,* as
an active ingredient to the monograph for OTC topical acne drug products
(21 CFR part 333, subpart D). The applicant requests that the ingredient
be available in both rinse-off (0.3 to 1.0 percent) and leave-on (0.2 to
0.5 percent) formulations. This TEA specifically requests the addition
of triclosan used in topical formulations (Ciba trade name IRGASAN DP
300) to 21 CFR part 333, subpart D. Other than the addition of a new
active ingredient in rinse-off and leave-on dosage forms, the TEA does
not request any other changes to the monograph.

**REVIEWER'S COMMENTS**

The applicant has provided basic information about triclosan including a
detailed chemical description as required in 21 CFR 330.14(c)(1)(i).
Additionally, the applicant points out that triclosan is listed in the
current version of the U.S. Pharmacopeia (USP)-National Formulary (NF).
According to 21 CFR 330.14(c)(1)(iii), reference to the current edition
of the USP-NF "may help satisfy the requirements of this section."

The applicant has selected 15 countries to serve as the basis of the TEA
(Table 1). The applicant states that triclosan has been marketed as an
active ingredient in topical acne drug products for at least 5
continuous years in each of these countries. In addition, triclosan has
been marketed in four countries (Australia, Japan, South Africa, and
Switzerland) listed in section 802(b)(1)(A)(i) of the Federal Food,
Drug, and Cosmetic Act and in France, Germany, and the United Kingdom of
the European Union (section 802(b)(1)(A)(ii) of the Federal Food, Drug,
and Cosmetic Act). The applicant states that, in the selected countries,
"acne products containing triclosan are sold OTC (directly to consumer)
and [not]{.underline} via prescription."

**TABLE 1.** **19 selected countries in which triclosan has been
marketed as an active ingredient in OTC topical acne drug products for 6
continuous years (1999-2004)**

+-----------------------------------------------------------------------+
|   -------------------------------- ---------------------------------  |
|   **Region**                       **Countries**                      |
|                                                                       |
|   Africa                           South Africa                       |
|                                                                       |
|   Asia                             China, India, Indonesia, Japan,    |
|                                    Korea, Malaysia, Philippines,      |
|                                    Singapore, Taiwan, Thailand,       |
|                                    Vietnam                            |
|                                                                       |
|   Australia                        Australia                          |
|                                                                       |
|   Europe                           France, Germany, Switzerland,      |
|                                    United Kingdom                     |
|                                                                       |
|   North America                    Mexico                             |
|                                                                       |
|   South America                    Brazil                             |
|   -------------------------------- ---------------------------------  |
+-----------------------------------------------------------------------+

The total number of dosage units sold in the selected countries was
calculated based on the total volume (kg) of topical triclosan (IRGASAN
DP 300) sold to finished **acne drug product manufacturers** each year.
The applicant specifically excluded sales of topical triclosan (IRGASAN
DP 300) to companies selling soaps (other than those specifically
marketed for the treatment of acne). The amounts of topical triclosan
sold to non-acne drug product (oral rinse, toothpaste, and antibacterial
soap) manufacturers is "a thousand times higher" according to the
applicant.

The applicant divided the amount of product sold each year by an
"average" ingredient concentration of 0.3 percent and estimated that a
"typical" dosage unit is equivalent to 100 grams of finished product. By
this method, the applicant estimates that approximately 21.5 million
dosage units have been sold in the selected countries since 1999. I note
that the listed concentration of triclosan in labels provided by the
applicant ranges twenty-fold from 0.05 percent to 1.0 percent. I also
note that the calculation to determine the minimum number of dosage
units in § 330.14(c)(2)(ii) is based on the largest package size
marketed. In addition, as noted above, the applicant states that the
amount of triclosan sold to soap manufacturers is much higher than is
sold strictly for acne drug products. Based on this estimate, the total
number of all triclosan-containing topical products, including soaps and
toothpastes containing triclosan, sold in the U.S. and around the world
for decades is at least in the tens of millions.

**TABLE 2.** **Estimated regional sales of triclosan (IRGASAN DP 300) as
an active ingredient in OTC topical acne drug products.**

Including the 19 selected countries and the countries (including the
United States) in which other triclosan-containing topical (non-acne)
and oral drug products are marketed, the population demographics
reflects the racial and ethnic diversity of the United States.

The applicant reports that it is unaware of any serious adverse drug
experiences (ADEs) in the selected countries, and no adverse events have
been reported in the medical literature dating back to 1976. The
applicant states that topical acne drug products containing triclosan
have not been withdrawn from the market in any country.

Thirty-six labels are provided as examples of labeling in 13 of the 19
selected countries. Warnings are included in the labeling for two
products (Clearasil and Clearex marketed in Japan). These warnings are
similar to those outlined in 21 CFR 333.350(c)(1) and (c)(2).
Directions, where provided, are similar to those specified in 21 CFR
333.350(d)(1) and (d)(2) for leave-on and rinse-off products,
respectively.

**RECOMMENDATION**

I recommend that triclosan be considered eligible for OTC drug review as
an active ingredient in the OTC topical acne drug products monograph (21
CFR Part 333, Subpart D):

• 0.2 to 0.5 percent in leave-on dosage form

• 0.3 to 1.0 percent in rinse-off dosage forms

These conditions have been marketed for a material time and to a
material extent in 19 selected countries on every continent except
Antarctica. The demographics of the 19 countries combined with that in
other countries in which this type of product as well as other
triclosan-containing topical and oral drug products have been marketed
reflects the population diversity found in the United States. An
estimated 21 million dosage units of topical acne treatments containing
triclosan have been sold in the selected countries during the six-year
period 1999-2004. Additionally, much larger quantities of triclosan are
used topically in antibacterial soaps and as antigingivitis ingredients
in oral rinses and toothpastes marketed worldwide without reported
adverse effect. The applicant states that no serious adverse drug
experiences have been reported for triclosan used specifically in the
treatment of acne, and no adverse events have been reported in the
medical literature dating back to 1976.