LEVULAN KERASTICK - DUSA

The metabolism of aminolevulinic acid ( ALA) is the first step in the biochemical pathway resulting in heme synthesis. Aminolevulinic acid is not a photosensitizer, but rather a metabolic precursor of protoporphyrin IX (PpIX), which is a photosensitizer. The synthesis of ALA is normally tightly controlled by feedback inhibition of the enzyme, ALA synthetase, presumably by intracellular heme levels. ALA, when provided to the cell, bypasses this control point and results in the accumulation of PpIX, which is converted into heme by ferrochelatase through the addition of iron to the PpIX nucleus.

According to the presumed mechanism of action, photosensitization following application of LEVULAN KERASTICK Topical Solution occurs through the metabolic conversion of ALA to PpIX, which accumulates in the skin to which LEVULAN Topical Solution has been applied. When exposed to light of appropriate wavelength and energy, the accumulated PpIX produces a photodynamic reaction, a cytotoxic process dependent upon the simultaneous presence of light and oxygen. The absorption of light results in an excited state of the porphyrin molecule, and subsequent spin transfer from PpIX to molecular oxygen generates singlet oxygen, which can further react to form superoxide and hydroxyl radicals. Photosensitization of actinic (solar) keratosis lesions using the LEVULAN KERASTICK, plus illumination with the BLU-U® Blue Light Photodynamic Therapy Illuminator (BLU-U), is the basis for LEVULAN photodynamic therapy (PDT).

In a human pharmacokinetic study (N=6) using a 128 mg dose of sterile intravenous ALA HCl and oral ALA HCl (equivalent to 100 mg ALA) in which plasma ALA and PpIX were measured, the mean half-life of ALA was 0.70 ± 0.18 h after the oral dose and 0.83 ± 0.05 h after the intravenous dose. The oral bioavailability of ALA was 50-60% with a mean Cmax of 4.65 ± 0.94 µg/mL. PpIX concentrations were low and were detectable only in 42% of the plasma samples. PpIX concentrations in plasma were quite low relative to ALA plasma concentrations, and were below the level of detection (10 ng/mL) after 10 to 12 hours.

ALA does not exhibit fluorescence, while PpIX has a high fluorescence yield. Time-dependent changes in surface fluorescence have been used to determine PpIX accumulation and clearance in actinic keratosis lesions and perilesional skin after application of LEVULAN KERASTICK Topical Solution in 12 patients. Peak fluorescence intensity was reached in 11 ± 1 h in actinic keratoses and 12 ± 1 h in perilesional skin. The mean clearance half-life of fluorescence for lesions was 30 ± 10 h and 28 ± 6 h for perilesional skin. The fluorescence in perilesional skin was similar to that in actinic keratoses. Therefore, LEVULAN KERASTICK Topical Solution should only be applied to the affected skin.

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.

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

LEVULAN Photodynamic Therapy for Actinic Keratoses.

The first step in LEVULAN KERASTICK photodynamic therapy (PDT) for actinic keratoses is application of the LEVULAN KERASTICK Topical Solution to actinic keratoses located on the patient’s face or scalp. After LEVULAN KERASTICK Topical Solution is applied to the actinic keratoses in the doctor’s office, the patient will be told to return the next day. During this time the actinic keratoses will become sensitive to light (photosensitive). Care should be taken to keep the treated actinic keratoses dry and out of bright light. After LEVULAN KERASTICK Topical Solution is applied, it is important for the patient to wear light-protective clothing, such as a wide-brimmed hat, when exposed to sunlight or sources of light. Fourteen to eighteen hours after application of LEVULAN KERASTICK Topical Solution the patient will return to the doctor’s office to receive blue light treatment, which is the second and final step in the treatment. Prior to blue light treatment, the actinic keratoses will be rinsed with tap water. The patient will be given goggles to wear as eye protection during the blue light treatment. The blue light is of low intensity and will not heat the skin. However, during the light treatment, which lasts for approximately 17 minutes, the patient will experience sensations of tingling, stinging, prickling or burning of the treated lesions. These feelings of discomfort should improve at the end of the light treatment. Following treatment, the actinic keratoses and, to some degree, the surrounding skin, will redden, and swelling and scaling may also occur. However, these lesion changes are temporary and should completely resolve by 4 weeks after treatment.

After LEVULAN KERASTICK Topical Solution is applied to the actinic keratoses in the doctor’s office, the patient should avoid exposure of the photosensitive actinic keratoses to sunlight or bright indoor light (e.g., from examination lamps, operating room lamps, tanning beds, or lights at close proximity) during the period prior to blue light treatment. If the patient feels stinging and/or burning on the actinic keratoses, exposure to light should be reduced. Before going into sunlight, the patient should protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect the patient against photosensitivity reactions.

If for any reason the patient cannot return for blue light treatment during the prescribed period after application of LEVULAN KERASTICK Topical Solution (14 to 18 hours), the patient should call the doctor. The patient should also continue to avoid exposure of the photosensitized lesions to sunlight or prolonged or intense light for at least 40 hours. If stinging and/or burning is noted, exposure to light should be reduced.

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.

No carcinogenicity testing has been carried out using ALA. 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 negative under 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 damage in 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.

Animal reproduction studies have not been conducted with ALA HCl. It is also not known whether LEVULAN KERASTICK Topical Solution can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. LEVULAN KERASTICK Topical Solution should be given to a pregnant woman only if clearly needed.

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

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. 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 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 Topical Solution application to photodamaged perilesional skin resulted in photosensitization of photodamaged skin and in a photodynamic response. (see Precautions).

Table 5 depicts the incidence and severity of cutaneous adverse events, stratified by anatomic site treated.

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 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.

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

Actinic keratoses targeted for treatment should be clean and dry prior to application of LEVULAN KERASTICK for Topical Solution.

Preparation:

The LEVULAN KERASTICK Topical Solution should be prepared as follows:

Step A - LEVULAN KERASTICK for Topical Solution Application 1.Hold the LEVULAN KERASTICK so that the applicator cap is pointing up.	Step A - LEVULAN KERASTICK for Topical Solution Application 2.Crush the bottom ampule containing the solution vehicle by applying finger pressure to Position A on the cardboard sleeve.
Step A - LEVULAN KERASTICK for Topical Solution Application 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.	Step A - LEVULAN KERASTICK for Topical Solution Application 4.Holding the LEVULAN KERASTICK between the thumb and forefinger, point the applicator cap away from the face, shake the LEVULAN KERASTICK 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 Preparation: Following solution admixture, remove the cap from the LEVULAN KERASTICK. 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 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 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 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.

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 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 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:
   • a)The patient’s nose should be no closer than 2” from the surface;
   • b)The patient’s forehead and cheeks should be no further than 4” from the surface;
   • c)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:
   • a)The patient’s scalp should be no closer than 2” from the surface;
   • b)The patient’s scalp should be no further than 4” from the surface;
   • c)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 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 for Topical Solution without subsequent BLU-U illumination is not recommended.