Levulan

The LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution, 20%, is a single-unit dosage form, supplied in packs of 6. Each LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution applicator consists of a plastic tube containing two sealed glass ampules and an applicator tip. One ampule contains 1.5 mL of solution vehicle. The other ampule contains 354 mg of aminolevulinic acid HCl. The applicator is covered with a protective cardboard sleeve and cap.

Storage Conditions: Store between 20°- 25 °C (68°- 77°F); excursions permitted to 15°- 30 °C (59°- 86 °F).The LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution should be used immediately following preparation (dissolution). Solution application must be completed within 2 hours of preparation. An applicator that has been prepared must be discarded 2 hours after mixing (dissolving) and a new LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution used, if needed.

Manufactured for: DUSA Pharmaceuticals, Inc. 25 Upton Drive Wilmington, MA 01887. FDA revision date: 7/11/2003

The LEVULAN KERASTICK (aminolevulinic acid) 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.

LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution 20% is intended for direct application to individual lesions diagnosed as actinic keratoses and not to perilesional skin. This product is not intended for application by patients or unqualified medical personnel. Application should involve either scalp or face lesions, but not both simultaneously. Therecommended treatment frequency is: one application of the LEVULAN KERASTICK (aminolevulinic acid) Topical Solution and one dose of illumination per treatment site per 8-week treatment session. Each individual LEVULAN KERASTICK (aminolevulinic acid) should be used for only one patient. Photodynamic therapy for actinic keratoses with LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution is a two stage process involving a) application of the product to the target lesions with LEVULAN KERASTICK (aminolevulinic acid) Topical Solution, followed 14 to 18 hours later by b) illumination with blue light using the BLU-U Blue Light Photodynamic Therapy Illuminator. The second visit, for illumination, must take place in the 14 18 hour window following application. Patients in clinical trials usually received application in the late afternoon, with illumination the following morning.

TABLE 6 - Schedule for LEVULAN and Blue Light Administration

Treated lesions that have not completely resolved after 8 weeks may be treated a second time with LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution Photodynamic

Therapy. Patients did not receive follow-up past 12 weeks after the initial treatment, so the incidence of recurrence of treated lesions past 12 weeks and the role of further treatment is not known.

Step A - LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution Application: Actinic keratoses targeted for treatment should be clean and dry prior to application of LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution.

Preparation

The LEVULAN KERASTICK (aminolevulinic acid) Topical Solution should be prepared as follows:

1. Hold the LEVULAN KERASTICK (aminolevulinic acid) so that the applicator cap is pointing up.

2. Crush the bottomampule containing the solution vehicle by applying finger pressure to Position A on the cardboard sleeve.

3. Crush the top ampule containing the ALA HCl powder by applying finger pressure to Position B on the cardboard sleeve. NOTE: To ensure both ampules are crushed continue crushing the applicator downward, applying finger pressure to Position A.

4. Holding the LEVULAN KERASTICK (aminolevulinic acid) between the thumb and forefinger, point the applicator cap away from the face, shake the LEVULAN KERASTICK (aminolevulinic acid) gently for at least 3 minutes to completely dissolve the drug powder in the solution vehicle. Do not press on the end cap while shaking.

LEVULAN KERASTICK (aminolevulinic acid) Preparation: Following solution admixture, remove the cap from the LEVULAN KERASTICK (aminolevulinic acid). The dry applicator tip should be dabbed on a gauze pad until uniformly wet with solution.

Application

Apply the solution directly to the target lesions by dabbing gently with the wet applicator tip. Enough solution should be applied to uniformly wet the lesion surface, including the edges without excess running or dripping. The effect of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution on ocular tissues is unknown. LEVULAN KERASTICK Topical Solution should not be applied to the periorbital area or allowed to contact ocular or mucosal surfaces. Once the initial application has dried, apply again in the same manner. The LEVULAN KERASTICK (aminolevulinic acid) Topical Solution must be used immediately following preparation (dissolution) due to the instability of the activated product. If the solution application is not completed within 2 hours of activation, the applicator should be discarded and a new LEVULAN KERASTICK for Topical Solution used.

Photosensitization of the treated lesions will take place over the next 14-18 hours. The actinic keratoses should not be washed during this time. The patient should be advised to wear a wide brimmed hat or other protective apparel to shade the treated actinic keratosis lesions from sunlight or other bright light sources until BLU-U treatment. The patient should be advised to reduce light exposure if the sensations of stinging and/or burning are experienced.

If for any reason the patient cannot be given BLU-U treatment during the prescribed time after LEVULAN KERASTICK (aminolevulinic acid) Topical Solution application, he or she may nonetheless experience sensations of stinging and/or burning if the photosensitized actinic keratoses are exposed to sunlight or prolonged or intense light at that time. The patient should be advised to wear a wide-brimmed hat or other protective apparel to shade the treated actinic keratosis lesions from sunlight or other bright light sources until at least 40 hours after the application of LEVULAN KERASTICK Topical Solution. The patient should be advised to reduce light exposure if the sensations of stinging and/or burning are experienced.

Step B - Administration of BLU-U Treatment 14 to 18 hours after application of LEVULAN

KERASTICK Topical Solution: At the visit for light illumination, the actinic keratoses to be treated should be gently rinsed with water and patted dry. Photoactivation of actinic keratoses treated with LEVULAN KERASTICK (aminolevulinic acid) Topical Solution is accomplished with BLU-U illumination from the BLU-U Blue Light Photodynamic Therapy Illuminator. A 1000 second (16 minutes 40 seconds) exposure is required to provide a 10 J/cm² light dose. During light treatment, both patients and medical personnel should be provided with blue blocking protective eyewear, as specified In the BLU-U Operating Instructions, to minimize ocular exposure. Please refer to the BLU-U Operating Instructions for further information on conducting the light treatment. Patients should be advised that transient stinging and/or burning at the target lesion sites occurs during the period of light exposure.

If blue light treatment with the BLU-U Blue Light Photodynamic Therapy Illuminator is interrupted or stopped for any reason, it should not be restarted and the patient should be advised to protect the treated lesions from exposure to sunlight or prolonged or intense light for at least 40 hours after application of the LEVULAN KERASTICK (aminolevulinic acid) Topical Solution from the first visit.

For patients with facial lesions:

1. The BLU-U Blue Light Photodynamic Therapy Illuminator is positioned so that the base is slightly above the patient's shoulder, parallel to the patient's face.
2. The BLU-U is positioned around the patient's head so the entire surface area to be treated lies between 2“ and 4“ from the BLU-U surface:
   1. The patient's nose should be no closer than 2“ from the surface;
   2. The patient's forehead and cheeks should be no further than 4“ from the surface;
   3. The sides of the patient's face and the patient's ears should be no closer than 2“ from the BLU-U surface.

A Chin Rest, available from DUSA Pharmaceuticals, Inc., may be used to provide support for the patient's head during treatment.

For patients with scalp lesions:

1. The knobs on either side of the BLU-U are loosened and the BLU-U is rotated to a horizontal position.
2. The BLU-U is positioned around the patient's head so the entire surface area to be treated lies between 2" and 4" from the BLU-U surface:
   1. The patient's scalp should be no closer than 2" from the surface;
   2. The patient's scalp should be no further than 4" from the surface;
   3. The sides of the patient's face and the patient's ears should be no closer than 2" from the BLU-U surface.

A Chin Rest, available from DUSA Pharmaceuticals, Inc., may be used to provide support for the patient's head during treatment.

LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution is not intended for use with any device other than the BLU-U Blue Light Photodynamic Therapy Illuminator. Use of LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution without subsequent BLU-U illumination is not recommended.

The LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution plus blue light illumination using the BLU-U 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 (aminolevulinic acid) for Topical Solution.

WARNINGS

The LEVULAN KERASTICK (aminolevulinic acid) 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 (aminolevulinic acid) 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 (aminolevulinic acid) 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 (aminolevulinic acid) Topical Solution outside the treatment site to eye or surrounding skin.

Application of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution to perilesional areas of photodamaged skin of the face or scalp may result in photosensitization. Upon exposure to activating light from the BLU-U Blue Light Photodynamic Therapy Illuminator, such photosensitized skin may produce a stinging and/or burning sensation and may become erythematous and/or edematous in a manner similar to that of actinic keratoses treated with LEVULAN PDT. Because of the potential for skin to become photosensitized, the LEVULANKERASTICK for Topical Solution should be used by a qualified health professional to apply drug only to actinic keratoses and not perilesional skin.

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

Carcinogenesis, Mutagenesis, Impairment to Fertility: No carcinogenicity testing has been carried out usingALA. No evidence of mutagenic effects was seen in four studies conducted with ALA to evaluate this potential. In the Salmonella-Escherichia coli/mammalian microsome reverse mutation assay (Ames mutagenicity assay), no increases in the number of revertants were observed with any of the tester strains. In the Salmonella-Escherichia coli/mammalian microsome reverse mutation assay in the presence of solar light radiation (Ames mutagenicity assay with light), ALA did not cause an increase in the number of revertants per plate of any of the tester strains in the presence or absence of simulated solar light. In the L5178Y TK± mouse lymphoma forward mutation assay, ALA was evaluated as negative with and without metabolic activation under the study conditions. PpIX formation was not demonstrated in any of these in vitro studies. In the in vivo mouse micronucleus assay, ALA was considered negativeunder the study exposure conditions. In contrast, at least one report in the literature has noted genotoxic effects in cultured rat hepatocytes after ALA exposure with PpIX formation. Other studies have documented oxidative DNA damagein vivo and in vitro as a result of ALA exposure.

No assessment of effects of ALA HCl on fertility has been performed in laboratory animals. It is unknown what effects systemic exposure to ALA HCl might have on fertility or reproductive function.

Pregnancy Category C: Animal reproduction studies have not been conducted with ALA HCl. It is also not known whether LEVULAN KERASTICK (aminolevulinic acid) Topical Solution can cause fetal harm whenadministered to a pregnant woman or can affect reproductive capacity. LEVULAN KERASTICK (aminolevulinic acid) Topical Solution should be given to a pregnant woman only if clearly needed.

Nursing Mothers: The levels of ALA or its metabolites in the milk of subjects treated with LEVULAN KERASTICK (aminolevulinic acid) Topical Solution have not been measured. Because many drugs are excreted in human milk, caution should be exercised when LEVULAN KERASTICK (aminolevulinic acid) Topical Solution is administered to a nursing woman.

SIDE EFFECTS

In Phase 3 studies, no non-cutaneous adverse events were found to be consistently associated with LEVULAN KERASTICK (aminolevulinic acid) Topical Solution application followed by blue light exposure.

Photodynamic Therapy Response: The constellation of transient local symptoms of stinging and/or burning, itching, erythema and edema as a result of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution plus BLUU treatment was observed in all clinical studies of LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution Photodynamic Therapy for actinic keratoses treatment. Stinging and/or burning subsided between 1 minute and 24 hours after the BLU-U Blue Light Photodynamic Therapy Illuminator was turned off, and appeared qualitatively similar to that perceived by patients with erythropoietic protoporphyria upon exposure to sunlight. There was no clear drug dose or light dose dependent change in the incidence or severity of stinging and/or burning.

In two Phase 3 trials, the sensation of stinging and/or burning appeared to reach a plateau at 6 minutes into the 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 majority of patients reported that all lesions treated exhibited at least slight stinging and/or burning. Less than 3% of patients discontinued light treatment due to stinging and/or burning.

The most common changes in lesion appearance after LEVULAN KERASTICK (aminolevulinic acid) 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. LEVULAN KERASTICK (aminolevulinic acid) Topical Solution application to photodamaged perilesional skin resulted in photosensitization of photodamaged skin and in a photodynamic response. (see PRECAUTIONS).

Other Localized Cutaneous Adverse Experiences: Table 5 depicts the incidence and severity of cutaneous adverse events, stratified by anatomic site treated.

TABLE 5- Post-PDT Cutaneous Adverse Events - ALA-018/ALA-019

Adverse Experiences Reported by Body System: In the Phase 3 studies, 7 patients experienced a serious adverse event. All were deemed remotely or not related to treatment. No clinically significant patterns of clinical laboratory changes were observed for standard serum chemical or hematologic parameters in any of the controlled clinical trials.

DRUG INTERACTIONS

There have been no formal studies of the interaction of LEVULAN KERASTICK (aminolevulinic acid) 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 (aminolevulinic acid) for Topical Solution.

In Phase 3 studies, no non-cutaneous adverse events were found to be consistently associated with LEVULAN KERASTICK (aminolevulinic acid) Topical Solution application followed by blue light exposure.

Photodynamic Therapy Response: The constellation of transient local symptoms of stinging and/or burning, itching, erythema and edema as a result of LEVULAN KERASTICK (aminolevulinic acid) Topical Solution plus BLUU treatment was observed in all clinical studies of LEVULAN KERASTICK (aminolevulinic acid) for Topical Solution Photodynamic Therapy for actinic keratoses treatment. Stinging and/or burning subsided between 1 minute and 24 hours after the BLU-U Blue Light Photodynamic Therapy Illuminator was turned off, and appeared qualitatively similar to that perceived by patients with erythropoietic protoporphyria upon exposure to sunlight. There was no clear drug dose or light dose dependent change in the incidence or severity of stinging and/or burning.

In two Phase 3 trials, the sensation of stinging and/or burning appeared to reach a plateau at 6 minutes into the 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 majority of patients reported that all lesions treated exhibited at least slight stinging and/or burning. Less than 3% of patients discontinued light treatment due to stinging and/or burning.

The most common changes in lesion appearance after LEVULAN KERASTICK (aminolevulinic acid) 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. LEVULAN KERASTICK (aminolevulinic acid) Topical Solution application to photodamaged perilesional skin resulted in photosensitization of photodamaged skin and in a photodynamic response. (see PRECAUTIONS).

Other Localized Cutaneous Adverse Experiences: Table 5 depicts the incidence and severity of cutaneous adverse events, stratified by anatomic site treated.

TABLE 5- Post-PDT Cutaneous Adverse Events - ALA-018/ALA-019

Adverse Experiences Reported by Body System: In the Phase 3 studies, 7 patients experienced a serious adverse event. All were deemed remotely or not related to treatment. No clinically significant patterns of clinical laboratory changes were observed for standard serum chemical or hematologic parameters in any of the controlled clinical trials.

LEVULAN KERASTICK (aminolevulinic acid) Topical Solution Overdose: LEVULAN KERASTICK (aminolevulinic acid) Topical Solution overdose have not been reported. In the unlikely event that the drug is ingested, monitoring and supportive care are recommended. The patient should be advised to avoid incidental exposure to intense light sources for at least 40 hours. The consequences of exceeding the recommended topical dosage are unknown.

BLU-U Light Overdose: There is no information on overdose of blue light from the BLU-U Blue Light Photodynamic Therapy Illuminator following LEVULAN KERASTICK Topical Solution application.