LEVULAN KERASTICK

1 INDICATIONS AND USAGE 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. LEVULAN KERASTICK for topical solution, a porphyrin precursor, plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator is indicated for photodynamic therapy (treatment) of minimally to moderately thick actinic keratoses of the face or scalp, or actinic keratoses of the upper extremities. ( 1 )

2 DOSAGE AND ADMINISTRATION LEVULAN KERASTICK photodynamic therapy is a two-stage process for administration by a health care provider.( 2.1 ) Apply the drug product to the target lesions. ( 2.1 ) Illuminate with blue light using the BLU-U ® Blue Light Photodynamic Therapy Illuminator after the incubation time of( 2.2 ): 14 to 18 hours for scalp or face 3 hours for upper extremities, with occlusion LEVULAN KERASTICK photodynamic therapy may be repeated a second time for lesions that have not completely resolved after 8 weeks ( 2.1 ) For topical use only. ( 2.1) See full prescribing information for complete dosage and administration instruction. ( 2 ) See BLU-U user manual for detailed lamp safety and operating instructions. ( 2.2 ) 2.1 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 1 The incubation time is 14-18 hours for actinic keratosis lesions on the face or scalp. 2 The incubation time is 3 hours for actinic keratosis lesions on the upper extremities. LEVULAN KERASTICK topical solution application Time window 1 for Blue Light Illumination for face or scalp Time window 2 for Blue Light Illumination for upper extremities 6 am 8 pm to Midnight 9 am 7 am 9 pm to 1 am 10 am 8 am 10 pm to 2 am 11 am 9 am 11 pm to 3 am 12 Noon 10 am Midnight to 4 am 1 pm 11 am 1 am to 5 am 2 pm 12 pm 2 am to 6 am 3 pm 1 pm 3 am to 7 am 4 pm 2 pm 4 am to 8 am 5 pm 3 pm 5 am to 9 am 6 pm 4 pm 6 am to 10 am 7 pm 5 pm 7 am to 11 am 8 pm 6 pm 8 am to Noon 9 pm 7 pm 9 am to 1 pm 10 pm 8 pm 10 am to 2 pm 11 pm 9 pm 11 am to 3 pm 12 Midnight 10 pm Noon to 4 pm 1 am 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. 2.2 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 containin…

5 WARNINGS AND PRECAUTIONS Transient amnestic episodes have been reported during postmarketing use of LEVULAN KERASTICK in combination with BLU-U Blue Light Photodynamic Therapy Illuminator. Inform patients and their caregivers that LEVULAN KERASTICK in combination with PDT may cause transient amnestic episodes. Advise them to contact the healthcare provider if the patient develops amnesia after treatment. ( 5.1 ) Avoid exposure of the photosensitive actinic keratoses to sunlight or bright indoor light prior to blue light treatment. Protect treated lesions from sunlight exposure. Sunscreens will not protect the patient against photosensitivity reactions. ( 5.2 ) The LEVULAN KERASTICK for topical solution should be used by a qualified health professional. To avoid unintended photosensitivity, LEVULAN KERASTICK topical solution should be applied to no more than 5 mm of perilesional skin surrounding each target actinic keratosis lesion. ( 5.2 ) Irritation may be experienced if this product is applied to eyes or mucous membranes. Do not apply to the eyes or to mucous membranes. Excessive irritation may be experienced if this product is applied under occlusion longer than 3 hours. ( 5.3 ) 5.1 Transient Amnestic Episodes Transient amnestic episodes have been reported during postmarketing use of LEVULAN KERASTICK in combination with BLU-U Blue Light Photodynamic Therapy Illuminator. Inform patients and their caregivers that LEVULAN KERASTICK in combination with PDT may cause transient amnestic episodes. Advise them to contact the healthcare provider if the patient develops amnesia after treatment. 5.2 Photosensitivity After LEVULAN KERASTICK topical solution has been applied, the treatment site will become photosensitive and 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) for 40 hours. Exposure may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Therefore, before exposure to sunlight, patients should protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material, and/or a long-sleeved shirt and/or gloves. 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 the eye or surrounding skin. Application of LEVULAN KERASTICK topical solution to perilesional areas of photodamaged skin of the face, scalp or upper extremities may result in photosensitization. Upon exposure to activating light from the BLU-U, 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 KERASTICK Photodynamic Therapy. Because of the potential for skin to become photosensitized, the LEVULAN KERASTICK topical solution should be used by a qualified health professional to apply drug to no more than 5mm of perilesional skin surrounding the target actinic keratosis lesions. If for any reason the patient cannot return for blue light treatment during the prescribed period after applying LEVULAN KERASTICK topical solution, 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. 5.3 Irritation The LEVULAN KERASTICK topical solution contains alcohol and is intended for topical use only. Irritation may be experienced if this product is applied to eyes or mucous membranes. Do not apply to the eyes or to mucous membranes. Excessive irritation may be experienced if this product is applied under occlusion longer than 3 hours. 5.4 Coagulation Defects The…

4 CONTRAINDICATIONS 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 [see Warnings and Precautions (5.2) ] Porphyria or known allergies to porphyrins [see Warnings and Precautions (5.2) ] Known sensitivity to any of the components of the LEVULAN KERASTICK. Cutaneous photosensitivity at wavelengths of 400-450 nm. ( 4 ) Porphyria or known allergies to porphyrins. ( 4 ) Sensitivity to any of the components of the LEVULAN KERASTICK. ( 4 )

7 DRUG INTERACTIONS 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 [see Warnings and Precautions (5.2) ] . 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. ( 7 )

8.1 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 [see Clinical Pharmacology (12.3) ]. 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 2% to 4% and 15% to 20%, respectively.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the other sections of the labeling: Transient Amnestic Episodes [see Warnings and Precautions (5.1) ] Increased Photosensitivity [see Warnings and Precautions (5.2) ] Irritation [see Warnings and Precautions (5.3) ] Coagulation defects [see Warnings and Precautions (5.4) ] The most common local adverse reactions (incidence ≥ 10%) were erythema, edema, stinging/burning, scaling/crusting, itching, erosion, hypo/hyperpigmentation, oozing/vesiculation/crusting, scaling and dryness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Dermatology at 877-533-3872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 [see Warnings and Precautions (5.2) ] . 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 Sca…