Levulan Drug Information

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 of the face, scalp, or upper extremities.

Preparation and Administration Overview

After mixing, the Levulan KERASTICK 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 lesions on the scalp, face or upper extremities; multiple lesions can be treated within a treatment region, but multiple treatment regions should not be treated simultaneously.

The recommended treatment frequency is: one application of the Levulan KERASTICK topical solution and one dose of illumination per treatment region per 8-week treatment session. Each individual Levulan KERASTICK applicator should be used for only one patient. Levulan KERASTICK photodynamic therapy for actinic keratoses is a two-stage process involving application of the Levulan KERASTICK topical solution to the target lesions and then illumination with blue light using the BLU-U Blue Light Photodynamic Therapy Illuminator after 3 hours for upper extremity lesions or after 14-18 hours for face or scalp lesions.

TABLE 1 Schedule for Levulan KERASTICK Photodynamic Therapy If for any reason the patient cannot be given BLU-U Blue Light Photodynamic Therapy Illuminator treatment during the prescribed time after applying Levulan KERASTICK topical solution, 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. Advise the patient to wear appropriate protective apparel (e.g., wide-brimmed hat, long sleeve shirt, gloves) to shade the treated actinic keratoses from sunlight or other bright light sources until at least 40 hours after the application of Levulan KERASTICK topical solution. Advise the patient to reduce light exposure if the sensations of stinging and/or burning are experienced.

Levulan KERASTICK photodynamic therapy may be repeated a second time for lesions that have not completely resolved 8 weeks after the initial treatment.

Dosage and Administration Instructions Step A - Treatment of Actinic Keratoses with Levulan KERASTICK Topical Solution Preparation of Lesions Actinic keratoses targeted for treatment should be clean and dry prior to application of Levulan KERASTICK Topical Solution. Preparation of Levulan KERASTICK topical solution The Levulan KERASTICK 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 aminolevulinic acid HCl as a dry solid. Levulan KERASTICK topical solution is prepared by crushing the glass ampoules and mixing the contents together. The Levulan KERASTICK topical solution can be prepared either manually, or using the optional KERASTICK KRUSHER™.

These methods are illustrated below. Figure 1: Manual Preparation: Hold the Levulan KERASTICK applicator with cap point up. Crush the bottom ampule containing the solution vehicle by applying finger pressure to Position A on the cardboard sleeve.

Crush the top ampule containing the ALA HCl powder by applying finger pressure to Position B on the cardboard sleeve. To ensure both ampules are crushed continue crushing the applicator downward, applying finger pressure to Position A. Shake the Levulan KERASTICK applicator gently for at least 30 seconds to completely dissolve the drug powder in the solution vehicle.

Figure 2: Optional KERASTICK KRUSHER Preparation: Open the KERASTICK KRUSHER and properly position one Levulan KERASTICK applicator into the KRUSHER making sure to orient the Levulan KERASTICK label “A” with the KRUSHER “A”. Firmly seat the Levulan KERASTICK applicator against the closed end of the KRUSHER (cap should be at open end). Once positioned properly, close and firmly press the top and bottom handles together until the top and bottom handles touch one another along their length.

A distinct crushing sound is made during this process. Ensure KRUSHER handles meet. The Levulan KERASTICK topical solution must be used within two hours of activation.

If the solution is not completely applied within 2 hours of the activation, discard the applicator. If needed, use a new Levulan KERASTICK applicator. Application of Levulan KERASTICK topical solution Application of Levulan KERASTICK topical solution to Face or Scalp Lesions: Following solution admixture, remove the cap from the Levulan KERASTICK applicator.

The dry applicator tip should be dabbed on a gauze pad until uniformly wet with solution. 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.

Once the initial application has dried, apply again in the same manner. Do not apply the Levulan KERASTICK topical solution to the periorbital area or allow it to contact ocular or mucosal surfaces. 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 keratoses from sunlight or other bright light sources until BLU-U Blue Light Photodynamic Therapy Illuminator treatment. At the visit for light illumination before treatment, the actinic keratoses treated with the Levulan KERASTICK topical solution should be gently rinsed with water and patted dry.

For Lesions on the Upper Extremities Following solution mixture, remove the cap from the Levulan KERASTICK applicator. Occlude the upper extremity with low density polyethylene plastic wrap and hold in place with an elastic net dressing. Figure 3: Method of Occlusion for Upper Extremities The patient should wear a long-sleeved shirt and/or gloves or other protective apparel to shade the treated actinic keratoses from sunlight or other bright light sources until BLU-U Blue Light Photodynamic Therapy Illuminator treatment.

Remove the occlusive dressing prior to light treatment and gently rinse the treated area(s) with water and pat dry before light illumination. Step B - Administration of BLU-U Treatment: Levulan KERASTICK is not intended for use with any device other than the BLU-U Blue Light Photodynamic Therapy Illuminator. Use of Levulan KERASTICK without subsequent BLU-U Blue Light Photodynamic Therapy Illuminator illumination is not recommended.

Photoactivation of actinic keratoses treated with Levulan KERASTICK topical solution is accomplished with illumination from the BLU-U Blue Light Photodynamic Therapy Illuminator. During light treatment, both patients and medical personnel should be provided with blue blocking protective eyewear, as specified in the BLU-U Blue Light Photodynamic Therapy Illuminator Operating Instructions. Please refer to the BLU-U Blue Light Photodynamic Therapy Illuminator 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 applying the Levulan KERASTICK topical solution. For patients with facial lesions: 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.

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. For patients with scalp lesions: The knobs on either side of the BLU-U are loosened and the BLU-U is rotated to a horizontal position. The BLU-U Blue Light Photodynamic Therapy Illuminator is positioned around the upper extremity so the entire surface area to be treated lies between 2” and 4” from the BLU-U surface.

A table may be used to support the upper extremities during light treatment. Lavulan-01 Lavulan-02 Levulan-03

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rate observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, no non-cutaneous adverse events were found to be consistently associated with LEVULAN KERASTICK photodynamic therapy. Photodynamic Therapy Response: The constellation of transient local symptoms of stinging and/or burning, itching, erythema and edema as a result of LEVULAN KERASTICK photodynamic therapy (PDT) was observed in all clinical trials 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. Local skin reactions at the application site were observed in 99% of subjects treated with LEVULAN KERASTICK topical solution and BLU-U Blue Light Photodynamic Therapy Illuminator.

The most common local adverse reactions (incidence ≥ 10%) were application site stinging/burning, erythema, edema, scaling/crusting, hypo/hyperpigmentation, itching, erosion, oozing/vesiculation/crusting, dryness. In the trials for face and scalp lesions, severe stinging and/or burning at one or more lesions during light treatment was reported by at least 50% of subjects. Severe stinging and/or burning also occurred during light treatment in 9% of subjects receiving treatment for upper extremity lesions.

The majority of subjects reported that all lesions treated exhibited at least slight stinging and/or burning. In trials of the face and scalp, the sensation of stinging/burning appeared to reach a plateau at 6 minutes into the treatment. Less than 3% of subjects receiving treatment for face or scalp lesions discontinued light treatment because of stinging/burning.

No subjects discontinued light treatment in the trial for upper extremity lesions. In trials for the face or scalp lesions, 99% of the active treatment group and 79% of the vehicle group experienced erythema shortly after treatment. In the trial for the upper extremity lesions, 99% of LEVULAN KERASTICK topical solution treatment group and 52% of the vehicle group experienced erythema on visit Days 2-3.

Approximately 35% of LEVULAN KERASTICK topical solution group had edema, while edema occurred in < 1% of the vehicle group. Both erythema and edema resolved to baseline or improved by 4 weeks after therapy for face or scalp. Edema resolved by 4 weeks and erythema resolved to baseline by 8 weeks for upper extremities.

The application of LEVULAN KERASTICK topical solution to perilesional skin resulted in stinging, burning, erythema and edema similar to treated actinic keratoses. Other Localized Cutaneous Adverse Experiences: Table 2 depicts the incidence and severity of cutaneous adverse events in trials for the face and scalp. TABLE 2 Post-PDT Cutaneous Adverse Events – ALA-018/ALA-019 For the Face and Scalp Table 3 depicts the incidence of other cutaneous adverse events in Phase 3 studies for the upper extremities.

TABLE 3 Percentage of Subjects with Cutaneous Adverse Reactions by the Most Severe Grade Reported Post-Baseline – CP0108 For Upper Extremities In the trial for upper extremity lesions, itching and scabbing occurred in 8% and 4%, respectively, of the subjects in the LEVULAN KERASTICK photodynamic therapy group. No subjects in the vehicle group reported itching or scabbing. Common ( > 2%, <10%) local cutaneous adverse reactions for face, scalp and upper extremities in the LEVULAN KERASTICK topical solution group included wheal, scabbing, pustules, ulceration, bleeding, tenderness and dysesthesia.

Uncommon (<2%) local cutaneous adverse reactions for face, scalp and upper extremities in the LEVULAN KERASTICK topical solution group were flaking, pain, peeling, perilesional pruritic rash, excoriation and blistering. Common ( > 2%, <10%) adverse reactions not limited to the application site for upper extremities and occurring more frequently in the LEVULAN KERASTICK topical solution group than in the vehicle group were sinusitis, squamous cell carcinoma, and squamous cell carcinoma of skin.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of LEVULAN KERASTICK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system disorders: transient amnestic episodes

There have been no formal studies of the interaction of LEVULAN KERASTICK 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 St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides and tetracyclines might increase the photosensitivity reaction of actinic keratoses treated with LEVULAN KERASTICK topical solution.

Pregnancy Risk Summary Limited available data with LEVULAN KERASTICK topical solution use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Animal developmental toxicology studies were not conducted with aminolevulinic acid. LEVULAN KERASTICK solution has low systemic absorption following topical administration, and the risk of maternal use resulting in fetal exposure to the drug is unknown.

The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Pediatric Use The safety and effectiveness in pediatric patients below the age of 18 have not been established. Actinic keratosis is not a disease generally seen in the pediatric population.

The LEVULAN KERASTICK 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 Known sensitivity to any of the components of the LEVULAN KERASTICK. Porphyria or known allergies to porphyrins.

LEVULAN KERASTICK Topical Solution Overdose In the 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 after ingestion. 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.