`----------------------------------CONTRAINDICATIONS----------------------
` 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------WARNINGS AND PRECAUTIONS-------------------
`
`
`● 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 (5.1).
`
`
`● 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. (5.1).
`
`● Irritation may be experienced if this product is applied to eyes or mucus
`
`
`
`
`
`
`
`
`
`
` 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 (5.2).
`
`
`
`
`
`
`
` -----------------------------ADVERSE REACTIONS ---------------------------
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` -----------------------------DRUG INTERACTIONS --------------------------
` 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).
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` LEVULAN® KERASTICK® safely and effectively. See full prescribing
`
`
`
`
`
`
`
` information for LEVULAN KERASTICK.
`
`
`
`
`
`
`
`
`
`
` LEVULAN KERASTICK (aminolevulinic acid HCl) for topical solution, 20%
`
` Initial U.S. Approval: 1999
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------------RECENT MAJOR CHANGES-------------------------
`
`
`
`
`
`
` Indications and Usage (1)
` 03/2018
` Dosage and Administration (2)
`
`
`
`
` 03/2018
`
`
` Warnings and Precautions (5.1, 5.2)
`
`
`
`
`
` 03/2018
`
`
`
`
` ------------------------------INDICATIONS AND USAGE----------------------------
`
` 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).
`
`
`
`
`
` -------------------------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):
`
`
`
`
`
`
`
`o
`
`
` 14 to 18 hours for scalp or face
`
`
`
`
`
`
`
`o
`
`
`
` 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.
`
` See BLU-U user manual for detailed lamp safety and operating instructions
`
`
`
`
`
`
`
`
`
`
`
`
` (2.2).
`
`
`
`
`
`
` ------------------------DOSAGE FORMS AND STRENGTHS ---------------------
`
`
`
` After mixture, topical solution contains 20% aminolevulinic acid hydrochloride
`
`
`
`
`
`
` (ALA HCl) by weight in a plastic applicator device (3).
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`
`
`
`
`
`1
`
`2
`
`
`6
`
`
`
`
` INDICATIONS AND USAGE
`
`
` DOSAGE AND ADMINISTRATION
`
` 2.1 Preparation and Administration Overview
`
`
`
`
` 2.2 Dosage and Administration Instructions
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`3
`
` CONTRAINDICATIONS
`
`4
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 Photosensitivity
`
`
`5.2
`
` Irritation
`
`
`
` 5.3 Coagulation Defects
`
` ADVERSE REACTIONS
`
` 6.1 Clinical Trial Experience
`
`
`
` 7. DRUG INTERACTIONS
`
`
` 8. USE IN SPECIFIC POPULATIONS
`
`
`
`
`
` 8.1 Pregnancy
`
`
` 8.2 Lactation
`
`
`
` 8.4 Pediatric Use
`
`
`
` 8.5 Geriatric Use
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 10 OVERDOSAGE
`
`
` LEVULAN KERASTICK Topical Solution Overdose
`
` 10.1
` BLU-U Light Overdose
`
`
` 10.2
`
`
`11 DESCRIPTION
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`
` 12.1 Mechanism of Action
`
`
`
`
` 12.2
` Pharmacodynamics
`
`
` 12.3
`
` Pharmacokinetics
` 13 NONCLINICAL TOXICOLOGY
`
`
`
`
` Carcinogenesis, Mutagenesis, Impairment of Fertility
` 13.1
`
` 14 CLINICAL STUDIES
`
`
`
`
`
`
`
`
`
` 14.1 Actinic Keratoses of the Face or Scalp
`
`
`
`
` 14.2 Actinic Keratoses of the Upper Extremities
`
`
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
` 16.1 How Supplied
`
`
`
`
` 16.2
` Product Package – NDC Number
`
`
`
` 16.3
`
` Storage
`
`
` 17 PATIENT COUNSELING INFORMATION
`
` *Sections or subsections omitted from the full prescribing information are
`
`
`
`
`
`
`
`
`
` not listed.
`
`
`
`
`
`
`
`
`
`
`
` Revised: 03/2018
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`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.
`
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
` 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.
`
`
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
`TABLE 1 Schedule for LEVULAN KERASTICK Photodynamic Therapy
`
`
`
`
`
` Time window1 for Blue Light
` Time window2 for Blue Light
`
`
`
`
`LEVULAN KERASTICK topical
`
` Illumination for face or scalp
`
` Illumination for upper extremities
`
`
` solution application
`
`
`
` 6 am
` 8 pm to Midnight
` 9 am
`
` 7 am
` 10 am
`
`
` 9 pm to 1 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
`
` 2 pm
`
` 1 am to 5 am
`
` 12 pm
`
` 2 am to 6 am
`
` 3 pm
`
`
` 3 am to 7 am
`
` 4 pm
` 1 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
`
`
`
` 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.
`
`
`
`
`
` 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 applying the LEVULAN
`
` KERASTICK topical solution.
`
`
`
` Preparation of LEVULAN KERASTICK topical solution
`
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
`
`
` 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:
`
`
`
`
`1. 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.
`
`
`2. 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:
`
`
`
`
`
`
`
`
`
`
`1. 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).
`2. 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.
`
`3. Remove the LEVULAN KERASTICK applicator from the Krusher and shake the LEVULAN
`
`
` KERASTICK applicator gently for at least 30 seconds to completely dissolve the drug powder in the
`
` solution vehicle.
`
`
` The LEVULAN KERASTICK topical solution must be used within two (2) 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.
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
`
`
` 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. 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 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. 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.
`
`
`
`
`
`
` 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. Photosensitization of the treated lesions will take place over the next 3 hours. The
`
`actinic keratoses should not be washed during this time. Remove the occlusive dressing prior to light
`
`
` treatment and gently rinse the treated area(s) with water and pat dry before light illumination.
`
`
`
`
`
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
` 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. 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 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:
`
` 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.
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
` For patients with upper extremity lesions:
`
`
`
`
`
` 1. The knobs on either side of the BLU-U Blue Light Photodynamic Therapy Illuminator are loosened and the
` light is rotated to a horizontal position.
`
`
`
` 2. 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.
`
`
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
`
`3
`
`
`
` DOSAGE FORM AND STRENGTHS
`
` For topical solution: 354 mg of aminolevulinic acid hydrochloride as a powder in a plastic applicator device.
`
`
`Upon mixture, LEVULAN KERASTICK is a topical solution containing 20% aminolevulinic acid
`
`
` hydrochloride (ALA HCl) by weight.
`
`
`
`
`
`
`
`
`
` 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 (5.1)]
`
`
`
`
` Porphyria or known allergies to porphyrins [see Warnings and Precautions (5.1)]
`
`
`
`
` Known sensitivity to any of the components of the LEVULAN KERASTICK.
`
`
`
`
`
`
`
`
` 5
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
` 5.1 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.
`
`Reference ID: 4230321
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
` 5.2 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 mucus 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 Coagulation Defects
`
` The LEVULAN KERASTICK for topical solution has not been tested on patients with inherited or acquired
`
`
` coagulation defects.
`
`
`
`
`
` 6
`
`
`
` ADVERSE REACTIONS
`
` The following adverse reactions are discussed in greater detail in the other sections of the labeling:
`
`● Increased Photosensitivity [see Warnings and Precautions (5.1)]
`
`
`
`
`● Irritation [see Warnings and Precautions (5.2)]
`
`
`
`
`● Coagulation defects [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
` 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 (5.1)].
`
`
`
`
`
`
`
` Other Localized Cutaneous Adverse Experiences: Table 2 depicts the incidence and severity of cutaneous
`
`
`
` adverse events in trials for the face and scalp.
`
`
`
`
`
`Reference ID: 4230321
`
`
`
`
`
`TABLE 2 Post-PDT Cutaneous Adverse Events – ALA-018/ALA-019 For the Face and Scalp
`
`
`
`
`
` FACE
`
`
`
` SCALP
`
`
`
`
`
`
`
` Degree of Severity
`
`
`
`
`
` Scaling/Crusting
`
` Pain
` Tenderness
`
` Itching
`
` Edema
` Ulceration
`
` Bleeding/Hemorrhage
`
` Hypo/hyper-pigmentation
`
`
` Vesiculation
`
` Pustules
`
` Oozing
`
` Dysesthesia
`
` Scabbing
`
` Erosion
` Excoriation
`
` Wheal/Flare
`
` Skin disorder NOS
`
`
`
`
`
` Vehicle + PDT
` (n=41)
`
`
`
`
`
`
`
` Severe
`
`
`
` Severe
`
` LEVULAN
`
`KERASTICK
`Topical Solution +
`
`
` PDT (n=139)
`
` Mild/
`
` Moderate
`
` 71%
` 1%
`
`
` 1%
` 25%
`
` 1%
`
`
` 4%
`
` 4%
`
`
` 1%
`
` 0%
`
` 0%
`
` 1%
`
` 0%
`
` 0%
`
` 0%
`
` Mild/
`
`
` Moderate
`
` 12%
` 0%
`
`
` 0%
`
` 7%
`
` 0%
`
` 0%
`
` 0%
`
` 22%
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 1%
`
` 1%
`
` 0%
`
` 1%
`
` 0%
`
`
` 4%
`
` 4%
`
` 1%
`
` 2%
`
` 2%
` 14%
`
` 1%
`
`
` 7%
`
` 5%
`
`
`
` 20%
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` Vehicle + PDT
`
`
` (n=21)
`
`
`
`
`
` Severe
`
`
`
` Severe
`
` LEVULAN
`
`KERASTICK
`
` Topical Solution +
`
`
` PDT (n=42)
`
` Mild/
`
` Moderate
`
` 64%
` 0%
`
`
` 2%
` 14%
`
` 0%
`
`
` 2%
`
` 2%
`
`
` 2%
`
` 0%
`
` 0%
`
` 7%
`
` 0%
`
` 0%
`
` 0%
`
` Mild/
`
`
` Moderate
`
` 19%
` 0%
`
`
` 0%
` 19%
`
` 0%
`
`
` 0%
`
` 0%
`
`
`
` 36%
`
`
`
` 33%
`
`
` 5%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 2%
`
` 0%
`
` 2%
` 12%
`
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 5%
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` 0%
`
` Table 3 depicts the percentage of subjects with cutaneous adverse reactions by the most severe grade reported
`
`
`
`
`
`
`
`
`
` in course of the trial for the upper extremity lesions.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Degree of Severity
`
` Edema
`
` Erythema
`
`
` Hyper-pigmentation
`
` Hypo-pigmentation
` Oozing/Vesiculation/
`
`
` Crusting
` Scaling and Dryness
`
` Stinging/Burning
`
`
`
`Reference ID: 4230321
`
` TABLE 3 Percentage of Subjects with Cutaneous Adverse Reactions by the Most Severe Grade
`Reported Post-Baseline – CP0108 For Upper Extremities
`
`
`
`
`
`
`LEVULAN KERASTICK
` Vehicle + PDT
`
`
`
` Topical Solution + PDT
`
` (N=134)
` (N=135)
`
`
` Moderate/
`
` Moderate/
`
` Severe
`
` Severe
`
` 4%
`
` 1%
` 65%
`
` 12%
`
` 9%
`
`
` 10%
`
` 4%
` 5%
`
`
`
`
` Minimal/
`
` Mild
`
` 51%
`
` 35%
`
` 64%
`
` 46%
`
`
`
` Total
`
`
` 56%
` 100%
`
` 73%
`
`
` 50%
`
`
` Minimal/
`
` Mild
`
` 7%
` 63%
`
`
` 57%
`
` 50%
`
`
`
`
`
` Total
`
`
` 8%
` 75%
`
`
` 66%
`
` 55%
`
`
` 36%
`
` 65%
`
` 23%
`
`
` 5%
` 22%
`
`
` 73%
`
`
` 41%
`
` 87%
`
` 96%
`
`
` 8%
` 58%
`
`
` 23%
`
`
` 2%
`
` 7%
`
` 0%
`
`
` 10%
`
` 64%
`
` 23%
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
` 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 (5.1)].
`
`
`
`
`
` USE IN SPECIFIC POPULATIONS
` 8
`
`
` 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.
`
`
` 6.2 Lactation
`
`
`
`
`
` Risk Summary
`
` There are no data on the presence of LEVULAN KERASTICK topical solution in either human or animal
`
`
`
`
`
`
`
`milk, the effects on the breastfed infant or on milk production. The developmental and health benefits of
`
`
`
`Reference ID: 4230321
`
`
`
` breastfeeding should be considered along with the mother’s clinical need for LEVULAN KERASTICK
`
`
`
`
` topical solution and any potential adverse effects on the breastfeeding child from LEVULAN KERASTICK
`
`
` topical solution or from the underlying maternal condition.
`
`
`
`
`
`
` 8.4 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.
`
`
`
`
`
` 8.5 Geriatric Use
`
`
` Of the 512 subjects in Phase 3 clinical trials of LEVULAN KERASTICK topical solution, 63% (321/512)
` were 65 years old and over, while 24% (123/512) were 75 years old and over. No overall differences in
`
`
`
`safety or substantial differences in effectiveness were observed between these subjects and younger subjects,
`
`but greater sensitivity of some older individuals cannot be ruled out.
`
`
`
`
` OVERDOSAGE
`
` 10.1 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