`
`
`
`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-------------------------­
`03/2018
`Indications and Usage (1)
`
`
`Dosage and Administration (2)
`03/2018
`
`
`Warnings and Precautions (5.2, 5.3)
`03/2018
`
`
`
`
`04/2018
`Warnings and Precautions (5.1)
`
`
`
`
`
`
`------------------------------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).
`
`
`----------------------------------CONTRAINDICATIONS----------------------­
`
`
` Cutaneous photosensitivity at wavelengths of 400-450 nm (4)
`
` Porphyria or known allergies to porphyrins (4)
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`1
`
`2
`
`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 Transient Amnestic Episodes
`
`5.2 Photosensitivity
`
`
`5.3
`Irritation
`
`5.4 Coagulation Defects
`ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`6.2 Postmarketing Experience
`
`7. DRUG INTERACTIONS
`
`
`8. USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`
`
`
`
`6
`
`
`
`
`
`
` Sensitivity to any of the components of the LEVULAN KERASTICK
`(4)
`
`------------------------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 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).
`
`
`-----------------------------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
`
`Revised: 04/2018
`
`
`
`
`
`
`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
`Pharmacokinetics
`12.3
`
`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.
`
`
`
`
`
`Reference ID: 4250822
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`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: 4250822
`
`

`

`
`
`TABLE 1 Schedule for LEVULAN KERASTICK Photodynamic Therapy
`
`
`LEVULAN KERASTICK topical
`Time window2 for Blue Light
`Time window1 for Blue Light
`Illumination for face or scalp
`Illumination for upper extremities
`solution application
`
`
`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
`10 pm
`9 am to 1 pm
`
`
`8 pm
`11 pm
`10 am to 2 pm
`
`
`9 pm
`12 Midnight
`11 am to 3 pm
`
`
`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: 4250822
`
`

`

`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: 4250822
`
`

`

`
`
` 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: 4250822
`
`

`

`
`
`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: 4250822
`
`

`

`
`
`
`DOSAGE FORM AND STRENGTHS
`3
`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 (5.2)]
`
`
`
` Porphyria or known allergies to porphyrins [see Warnings and Precautions (5.2)]
`
`
` Known sensitivity to any of the components of the LEVULAN KERASTICK.
`
`WARNINGS AND PRECAUTIONS
`
`
`
`5
`
`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.
`
`
`
`Reference ID: 4250822
`
`

`

`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 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.
`
`5.4 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:
`● 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)]
`
`
`
`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: 4250822
`
`

`

`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.
`
`
`
`Reference ID: 4250822
`
`
`
`

`

`LEVULAN
`LEVULAN
`Vehicle + PDT
`KERASTICK
`Vehicle + PDT
`
`KERASTICK
`(n=21)
`Topical Solution +
`(n=41)
`Topical Solution +
`PDT (n=42)
`PDT (n=139)
`
`
`
`Moderate Severe Mild/ Mild/ Moderate Severe Mild/ Moderate Severe Mild/ Moderate
`
`71%
`1%
`12%
`0%
`64%
`2%
`19%
`1%
`0%
`0%
`0%
`0%
`0%
`0%
`1%
`0%
`0%
`0%
`2%
`0%
`0%
`25%
`1%
`7%
`0%
`14%
`7%
`19%
`1%
`0%
`0%
`0%
`0%
`0%
`0%
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`
`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
`
`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.
`
`
`33%
`
`Severe
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`
`TABLE 2 Post-PDT Cutaneous Adverse Events – ALA-018/ALA-019 For the Face and Scalp
`
`FACE
`SCALP
`
`
`
`
`
`
`
`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%
`
`36%
`
`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%
`
`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%
`
`
`
`Degree of Severity
`
`Edema
`Erythema
`Hyper-pigmentation
`Hypo-pigmentation
`Oozing/Vesiculation/
`Crusting
`Scaling and Dryness
`Stinging/Burning
`
`Reference ID: 4250822
`
`

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`
`
`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.
`6.2 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
`
`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)].
`
`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
`
`
`
`Reference ID: 4250822
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`

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`
`
`recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
`8.2 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
`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 to intense light sources for at least 40 hours after ingestion. The
`consequences of exceeding the recommended topical dosage are unknown.
`10.2 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.
`
`DESCRIPTION
`11
`LEVULAN® KERASTICK® (aminolevulinic acid HCl) for topical solution, 20%, a porphyrin precursor,
`contains the hydrochloride salt of aminolevulinic acid (ALA), an endogenous 5-carbon aminoketone.
`ALA HCl is a white to off-white, odorless crystalline solid that is very soluble in water, slightly soluble in
`methanol and ethanol, and practically insoluble in chloroform, hexane and mineral oil.
`The chemical name for ALA HCl is 5-amino-4-oxopentanoic acid hydrochloride (MW = 167.59). The
`structural formula is represented below:
`
`Reference ID: 4250822
`
`
`
`

`

`
`
`
`
`The LEVULAN KERASTICK for topical solution applicator is a two-component system consisting of a
`plastic tube containing two sealed glass ampules and an applicator tip. One ampule contains 1.5 mL of
`solution vehicle comprising alcohol USP (ethanol content = 48% v/v), water, laureth-4, isopropyl alcohol, and
`polyethylene glycol. The other ampule contains 354 mg of aminolevulinic