FDA Sends Warning Letter to DUSA Pharmaceuticals Over Actinic Keratosis Treatment Ad

ROCKVILLE, Md., April 26, 2007-The FDA today posted on its website a warning letter sent to DUSA Pharmaceuticals, Inc. about an advertisement for Levulan Kerastick for Topical Solution 20%. The letter is below.


D. Geoffrey Shulman, MD, FRCPC
Chairman of the Board and Chief Executive Officer
DUSA Pharmaceuticals, Inc.
25 Upton Drive
Wilmington, MA 01887

RE: NDA # 20-965
Levulan® Kerastick® (aminolevulinic acid HCl) for Topical Solution, 20%
MACMIS ID # 15170
WARNING LETTER

Dear Dr. Shulman:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food and
Drug Administration (FDA) has reviewed an advertisement (MKT-1330 Rev C) for Levulan
Kerastick (aminolevulinic acid HCl) for Topical Solution, 20% (Levulan Kerastick) submitted by
DUSA Pharmaceuticals, Inc. (DUSA) under cover of Form FDA 2253. The advertisement is false or
misleading because it presents efficacy claims for Levulan Kerastick, but omits and minimizes the
risks associated with the use of the drug, broadens the indication, and overstates the efficacy of the
drug. Therefore, the advertisement misbrands Levulan Kerastick in violation of the Federal Food,
Drug, and Cosmetic Act (Act), 21 U.S.C. §§ 352(n) and 321(n), and FDA’s implementing
regulations. See 21 CFR 202.1(e)(5); (e)(6)(i). This advertisement raises significant public health
and safety concerns because it suggests that Levulan Kerastick is safer and more effective than has
been demonstrated by substantial evidence or substantial clinical experience.

Background
According to the product labeling (PI):
The LEVULAN KERASTICK for Topical Solution plus blue light illumination using the BLUU
Blue Light Photodynamic Therapy Illuminator is indicated for the treatment of minimally to
moderately thick actinic keratoses (Grade 1 or 2, see table 2 for definition) of the face or scalp.
According to table 2, Grade 1 lesions are defined as slightly palpable actinic keratoses that are better
felt than seen and Grade 2 lesions are moderately thick actinic keratoses that are easily seen and felt.

The PI also includes the following risk information (in pertinent part):
CONTRAINDICATIONS
The LEVULAN KERASTICK for Topical Solution plus blue light illumination using the BLUU
Blue Light Photodynamic Therapy Illuminator is contraindicated in patients with cutaneous
photosensitivity at wavelengths of 400-450 nm, porphyria or known allergies to porphyrins,
and in patients with known sensitivity to any of the components of the LEVULAN
KERASTICK for Topical Solution.

WARNINGS
The LEVULAN KERASTICK for Topical Solution contains alcohol and is intended for topical
use only. Do not apply to the eyes or to mucous membranes. Excessive irritation may be
experienced if this product is applied under occlusion.

PRECAUTIONS
General:
During the time period between the application of LEVULAN KERASTICK Topical
Solution and exposure to activating light from the BLU-U Blue Light Photodynamic Therapy
Illuminator, the treatment site will become photosensitive. After LEVULAN KERASTICK
Topical Solution application, patients should avoid exposure of the photosensitive treatment
sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning
beds, or lights at close proximity) during the period prior to blue light treatment. Exposure may
result in a stinging and/or burning sensation and may cause erythema and/or edema of the
lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the
sun by wearing a wide-brimmed hat or similar head covering of light-opaque material.
Sunscreens will not protect against photosensitivity reactions caused by visible light. It has not
been determined if perspiration can spread the LEVULAN KERASTICK Topical Solution
outside the treatment site to eye or surrounding skin.

The LEVULAN KERASTICK for Topical Solution has not been tested on patients with
inherited or acquired coagulation defects.

Drug Interactions:
There have been no formal studies of the interaction of LEVULAN KERASTICK
for Topical Solution with any other drugs, and no drug-specific interactions were noted during
any of the controlled clinical trials. It is, however, possible that concomitant use of other
known photosensitizing agents such as griseofulvin, thiazide diuretics, sulfonylureas,
phenothiazines, sulfonamides and tetracyclines might increase the photosensitivity reaction of
actinic keratoses treated with the LEVULAN KERASTICK for Topical Solution.
Finally, the Adverse Reactions section of the PI states:
The constellation of transient local symptoms of stinging and/or burning, itching, erythema and
edema as a result of LEVULAN KERASTICK Topical Solution plus BLU-U treatment was
observed in all clinical studies of LEVULAN KERASTICK for Topical Solution

Photodynamic Therapy for actinic keratoses treatment….. Severe stinging and/or burning at
one or more lesions being treated was reported by at least 50% of the patients at some time
during treatment….The most common changes in lesion appearance after LEVULAN
KERASTICK Topical Solution Photodynamic Therapy were erythema and edema. In 99% of
active treatment patients, some or all lesions were erythematous shortly after treatment, while
in 79% of vehicle treatment patients, some or all lesions were erythematous. In 35% of active
treatment patients, some or all lesions were edematous, while no vehicle-treated patients had
edematous lesions. Both erythema and edema resolved to baseline or improved by 4 weeks
after therapy.

The most common adverse events associated with Levulan Kerastick were: Scaling/Crusting (71%
face and 64% scalp of mild/moderate severity), Hypo/hyper-pigmentation (22% face and 36% scalp),
and Itching (25% face and 14% scalp of mild/moderate severity).
Omission and Minimization of Risk Information

Promotional materials are misleading if they fail to reveal facts that are material in light of the
representations made by the materials or with respect to consequences that may result from the use of
the drug as recommended or suggested by the materials. The advertisement is misleading because it
presents claims for Levulan Kerastick but fails to present any risk information.

The advertisement includes the following claims:
• “Treats AKs without weeks of red, raw skin”
• “94% rated cosmetic response as good to excellent”
• “This is why 4 out of 5 patients prefer Levulan to previous 5-FU treatments”
(original emphasis)

However, the advertisement entirely omits risk information for Levulan Kerastick, including the most
serious and frequently occurring risks associated with the drug. The statement, “See attached full
prescribing information for additional details” in very small type at the lower left-hand corner of the
advertisement does not mitigate this misleading presentation. As a result, the advertisement
misleadingly suggests that Levulan Kerastick is safer than has been demonstrated by substantial
evidence or substantial clinical experience.

In addition to omitting the risks associated with Levulan Kerastick, the advertisement also presents
claims that minimize risks associated with Levulan Kerastick use. Specifically, the advertisement
claims, “Treats AKs without weeks of red, raw skin. Instead, skin response usually subsides within
a week of treatment….” This claim is inconsistent with the Adverse Reactions section of the PI, which
states, “Both erythema and edema resolved to baseline or improved by 4 weeks after therapy.”
(emphasis added.)

Broadening of Indication
The advertisement is also misleading because it suggests that Levulan Kerastick is safe and effective
for use in a broader patient population or under broader conditions than has been demonstrated by
substantial evidence or substantial clinical experience. The advertisement contains representations that
promote the use of Levulan Kerastick to treat the broad population of patients with “AK.” For
example, the advertisement claims that Levulan photodynamic therapy “Treats AKs without weeks of
red, raw skin.” The PI identifies limitations to the use of Levulan Kerastick for actinic keratoses.
Specifically, according to the Indications and Usage section, “The LEVULAN KERASTICK for
Topical Solution plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy
Illuminator is indicated for the treatment of minimally to moderately thick actinic keratoses (Grade 1
or 2, see table 2 for definition) of the face or scalp.” According to table 2, Grade 1 lesions are defined
as slightly palpable actinic keratoses that are better felt than seen and Grade 2 lesions are moderately
thick actinic keratoses that are easily seen and felt. Levulan Kerastick was not studied, and therefore is
not indicated for Grade 3 lesions that are defined as very thick and/or hyperkeratotic actinic keratoses.
In addition, Levulan Kerastick is only indicated for the face or scalp. By failing to identify the
limitations to its indication, this claim implies that Levulan Kerastick is useful for the treatment of all
patients with actinic keratoses when this is not the case.

Overstatement of Efficacy
The advertisement includes the claim, “This is why 4 out of 5 patients prefer Levulan to previous 5-
FU treatments.” This claim is misleading for the following reasons. The reference cited to support
this claim is a study conducted in 27 patients who were asked one question about the acceptability of
Levulan Kerastick therapy on a 3-Point Comparability Scale comparing Levulan Kerastick to patients'
other prior therapies for actinic keratosis. This is an open-label study that does not directly compare
Levulan Kerastick with its competitors. Accordingly, there are many reasons for a stated preference
for the more recent treatment other than actual superiority. For example, patients may have preferred
Levulan Kerastick because they were a subgroup of people who took 5-FU without good response.
They may have also stated a preference for Levulan Kerastick because they recalled the more recent
treatment better, because they liked the investigator, because the treatment was free, or for a variety of
other reasons that are not actually related to the treatment. Additionally, patient “preference”
encompasses multiple aspects of patient experiences with the drugs such as efficacy, side effects,
dosing, and ease of administration and therefore cannot be adequately measured by one single item.
Such a claim should be based on evidence from an adequate and well-controlled study or studies using
validated and well-developed instruments to demonstrate that patients indeed prefer Levulan Kerastick
to 5-FU treatments.

Conclusion and Requested Action
For the reasons discussed above, your advertisement misbrands Levulan Kerastick in violation of the
Federal Food, Drug, and Cosmetic Act (Act), 21 U.S.C. §§ 352(n) and 321(n), and FDA’s
implementing regulations. See 21 CFR 202.1(e)(5); (e)(6)(i).
DDMAC requests that DUSA immediately cease the dissemination of violative promotional materials
for Levulan Kerastick such as those described above. Please submit a written response to this letter on
or before May 4, 2007, stating whether you intend to comply with this request, listing all violative
promotional materials for Levulan Kerastick the same as or similar to those described above, and
explaining your plan for discontinuing use of such materials. Because the violations described above
are serious, we request, further, that your submission include a comprehensive plan of action to
disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in
this letter to the audience(s) that received the violative promotional materials. Please direct your
response to me at the Food and Drug Administration, Center for Drug Evaluation and Research,
Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville,
MD 20705-1266, facsimile at 301-796-9877. In all future correspondence regarding this matter, please
refer to the MACMIS #15170 in addition to the NDA number. We remind you that only written
communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your
responsibility to ensure that your promotional materials for Levulan Kerastick comply with each
applicable requirement of the Act and FDA implementing regulations. Furthermore, claims regarding
the use of the BLU-U Blue Light Photodynamic Therapy Illuminator device alone were not evaluated
by DDMAC. It is also your responsibility to ensure that promotional claims regarding the device
comply with the applicable requirements of the Act and FDA implementing regulations.
Failure to correct the violations discussed above may result in FDA regulatory action, including
seizure or injunction, without further notice.

Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, R.Ph., M.B.A.
Director
Division of Drug Marketing,
Advertising, and Communications
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This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
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/s/
---------------------
Thomas Abrams
4/20/2007 12:50:06 PM

Posted: April 2007


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