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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

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| **PHARMACOLOGICAL CLASS**        | U |                                   |
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| **MONOGRAPH**                    |   | OTC Sunscreen Drug Products (21   |
|                                  |   | CFR part 352)                     |
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| **APPLICANT**                    |   | Ciba Specialty Chemicals          |
|                                  |   | Corporation                       |
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|                                  |   | Home and Personal Care Business   |
|                                  |   | Line                              |
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|                                  |   | 4090 Premier Drive                |
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|                                  |   | High Point, NC 27265              |
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| **SUBMISSION DATE**              |   | April 11, 2005                    |
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| **RECEIVED DATE**                |   | April 12, 2005                    |
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| **REVIEW DATE**                  |   | April 13, 2005                    |
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| **REVIEWER**                     |   | Michael L. Koenig, Ph.D.          |
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| **TEAM LEADER**                  |   | Matthew R. Holman, Ph.D.          |
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**BACKGROUND**

The applicant requests addition of bisoctrizole, up to 10 percent*,* as
a single active ingredient and in combination with other sunscreen
active ingredients, to the monograph for OTC sunscreen drug products (21
CFR part 352). This TEA does not request any changes (e.g., labeling or
testing) to the sunscreen monograph other than addition of bisoctrizole.
It is important to note that the applicant claims bisoctrizole protects
against both UVA and UVB radiation.

Before submitting the TEA, the applicant submitted a citizen petition
(CP13 in Docket Number 1978N-0038) in September 2000 The petition
requested the addition of TINOSORB^®^ M, which includes bisoctrizole and
4 inactive ingredients, to the sunscreen monograph. The petition also
included a request to add another sunscreen ingredient, TINOSORB^®^ S
(bemotrizinol), to the sunscreen monograph. In our April 2002 response
letter, FDA stated that the applicant should use the new TEA process (67
FR 3060, January 23, 2002) rather than a petition to add these
ingredients to the monograph. As directed by FDA, the applicant
submitted a TEA for both TINOSORB M and TINOSORB S on May 21, 2002. On
July 15, 2002, FDA informed the applicant that we could not find either
ingredient eligible for the OTC drug review, because neither ingredient
had been "marketed for a minimum of five continuous years," as required
in 21 CFR 330.14(b)(2). Both ingredients had only been marketed for 2.5
years at that time. The applicant submitted the current TEAs on April
11, 2005, because bisoctrizole (and bemotrizinol) have now been marketed
for 5 continuous years.

**REVIEWER'S COMMENTS**

The applicant has provided basic information about bisoctrizole
including a detailed chemical description as required in 21 CFR
330.14(c)(1)(i). Although bisoctrizole is not included in the U.S.
Pharmacopeia (USP)-National Formulary (NF), the applicant submitted a
draft monograph to the USP on April 23, 2004. According to the
applicant, USP is currently reviewing the draft monograph.

Bisoctrizole has been marketed for varying lengths of time in 39
countries on every continent except Antarctica and for at least 5
continuous years in 9 of these countries. The applicant has selected 7
countries to serve as the basis of the TEA based on the volume of sales
and variety of products available in these countries: Australia, Brazil,
France, Germany, Greece, Spain, and Switzerland (Table 1). Bisoctrizole
has been marketed continuously in each of these countries except
Australia since 2000 (i.e., 5 years). The applicant elected to include
marketing information for Australia, in which bisoctrizole has only been
marketed for 2 years, because Australian regulations regarding
sunscreens are similar to those in the United States. Two of the 7
selected countries, Australia and Switzerland, are listed in
section 802(b)(1)(A)(i) of the Federal Food, Drug, and Cosmetic Act (the
act). Four other selected countries (France, Germany, Greece, and
Spain - all in the European Union), are listed in section
802(b)(1)(A)(ii) of the act. The applicant states that, in all 39
countries, sunscreen products containing bisoctrizole are sold directly
to consumers without a prescription and are "not regulated as drugs."
However, FDA notes that sunscreens are regulated as OTC medicines by the
Therapeutic Goods Administration in Australia (one of the selected
countries).

**TABLE 1.** **Countries in which bisoctrizole has been marketed (7
selected countries appear in bold print)**

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|   ------------------- ----------------------------------------------  |
|   **Continent**       **Countries**                                   |
|                                                                       |
|   Africa              South Africa                                    |
|                                                                       |
|   Asia                China, Hong Kong, India, Indonesia, Iran,       |
|                       Japan, Korea, Malaysia^1^, Philippines,         |
|                       Singapore, Sri Lanka, Taiwan, Thailand, Turkey  |
|                                                                       |
|   Australia           **Australia**                                   |
|                                                                       |
|   Europe              Austria, Belarus, Belgium, Denmark, Finland,    |
|                       **France**^1^, **Germany**^1^, **Greece**^1^,   |
|                       Italy, Poland, Slovenia, **Spain**^1^,          |
|                       **Switzerland**^1^, Ukraine, United Kingdom     |
|                                                                       |
|   North America       Guatemala, Mexico                               |
|                                                                       |
|   South America       Argentina^1^, Bolivia, **Brazil**^1^,           |
|                       Columbia^1^, Ecuador, Peru                      |
|   ------------------- ----------------------------------------------  |
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^1^ Bisoctrizole has been marketed for 5 continuous years in these
countries.

The applicant indicates that bisoctrizole is most commonly marketed in
combination with other sunscreen active ingredients. Formulations
marketed in different countries include bisoctrizole and other monograph
active ingredients (e.g. avobenzone, titanium dioxide) and/or other
active ingredients under consideration for inclusion in the sunscreen
monograph (e.g. amiloxate, enzacamene).

Detailed information about the population demographics in each of the 7
selected countries is provided in Appendix 1 of the TEA. Considering
these 7 countries together with the other countries listed in Table 1,
the population demographics appear to reflect the diversity of the U.S.
population.

The applicant reports that it is unaware of any adverse drug experiences
(ADEs) in any of the countries in which bisoctrizole-containing
sunscreens have been marketed. The applicant also states that sunscreen
products containing bisoctrizole have not been withdrawn from the market
in any country.

Examples of labeling are provided for products sold in Europe (22
labels), South America (4 labels), Asia (3 labels), and Australia (1
label). The indications, warnings, and directions included in the
labeling from these countries are comparable to those outlined in 21 CFR
352.52(b), (c), and (d), respectively.

The applicant calculated the total number of dosage units containing
bisoctrizole sold in the 7 selected countries according to 21 CFR
330.14(c)(ii)(B). This paragraph stipulates that applicants can estimate
the total number of dosage units sold for each dosage form by dividing
the total weight of the active ingredient sold by the total weight of
the active ingredient in the largest package size marketed. The sponsor
used the average concentration (2.5%), rather than the highest
concentration (10%), of bisoctrizole contained in the marketed products.
Use of the average concentration seems appropriate, because it is
reflective of the concentrations listed in the submitted labeling. By
this method, the applicant estimates that approximately 57.5 million
dosage units of sunscreen containing bisoctrizole were sold in the 7
selected countries between 2000 and 2004 (Table 2). Moreover, 68.3
million dosage units were sold worldwide during this period. If the
highest concentration of bisoctrizole were used in the calculation, an
estimated 14.4 million units of bisoctrizole-containing sunscreens were
sold in the 7 selected countries and approximately 17 million were sold
worldwide.

**TABLE 2.** **Estimated regional sales of bisoctrizole in sunscreen
drug products (2000 - 2004)**

**RECOMMENDATION**

I recommend that bisoctrizole, up to a maximum concentration of 10
percent, be considered eligible for the OTC drug review. Bisoctrizole
should be eligible as a single active ingredient and in combination with
other active ingredients in the OTC sunscreen monograph (21 CFR part
352). Bisoctrizole has been marketed, primarily in combination, "for a
material time" and "to a material extent" in 1 South American and 5
European countries. The demographics of these countries, especially when
combined with other countries in which this ingredient has been marketed
as a sunscreen, adequately reflects the diversity of the U.S.
population. At least 14.4 million dosage units of sunscreens containing
bisoctrizole have been sold in 7 selected countries on 3 continents
during 2000-2004. Furthermore, at least 17 million dosage units have
been sold in 39 countries on every continent except Antarctica. The
applicant states that no serious adverse drug experiences have been
reported for sunscreen products containing bisoctrizole. The sponsor
should be advised of the following:

-   an official or proposed USP monograph must be included with data and
    information demonstrating the safety and effectiveness of this
    ingredient, in accordance with 21 CFR 330.14(i)

-   safety and effectiveness data are required for bisoctrizole as a
    single active ingredient and bisoctrizole in combination with GRASE
    active ingredients