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
`
`-------------------------INDICATIONS AND USAGE-----------------------------
`
`The LEVULAN KERASTICK for Topical Solution, a porphyrin precursor,
`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 or scalp (1).
`---------------------DOSAGE AND ADMINISTRATION ----------------------
`Photodynamic therapy for actinic keratoses with LEVULAN KERASTICK
`for Topical Solution is a two stage process involving a) application of the
`product to the target lesions with LEVULAN KERASTICK Topical
`Solution, followed 14 to 18 hours later by b) illumination with blue light
`
`using the BLU-U® Blue Light Photodynamic Therapy Illuminator. Treated
`
`
` lesions that have not completely resolved after 8 weeks may be treated a
`
`second time with LEVULAN KERASTICK for Topical Solution
`
`
`Photodynamic Therapy (2).
`--------------------DOSAGE FORMS AND STRENGTHS ---------------------
`Solution containing 20% aminolevulinic acid hydrochloride (ALA.HCl) by
`
`weight in a plastic applicator device (3).
`------------------------------CONTRAINDICATIONS----------------------------
`
`Cutaneous photosensitivity at wavelengths of 400-450 nm (4).
`
`
`
`Full Prescribing Information: Contents*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`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 Trials Experience
` DRUG INTERATIONS
`7.
`8. USE IN SPECIFIC POPULATIONS
`
`
` Pregnancy
`8.1
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
` Geriatric Use
`
`
`
`
`6
`
`
`
`
`
`----------------------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 apply drug only to actinic keratoses
`
`and not perilesional skin (5.2).
`
`
`•
`
`
`•
`
`Do not apply to the eyes or to mucous membranes. Excessive irritation
`
`may be experienced if this product is applied under occlusion (5.2).
`-----------------------------ADVERSE REACTIONS -----------------------------­
`Adverse reactions occurring during clinical trials with an incidence ≥ 2%
`
`
`were erythema, edema, stinging/burning, scaling/crusting,
`hypo/hyperpigmentation, itching/pruritus, erosion, wheal/flare, vesiculation,
`
`
`ulceration, bleeding/hemorrhage, pain, pustules, tenderness, scabbing and
`dysesthesia (6).
`
`To report SUSPECTED ADVERSE REACTIONS, contact DUSA
`
`Pharmaceuticals, Inc. at (877) 533-3872 or FDA at (800) FDA-1088 or
`www.fda.gov/medwatch
`
`-----------------------------DRUG INTERACTIONS -----------------------------­
`
`There have been no formal studies of the interaction of LEVULAN
`
`KERASTICK for Topical Solution with any other drugs, and no drug-
`specific interactions were noted during any of the controlled clinical trials. It
`is, however, possible that concomitant use of other known photosensitizing
`
`agents such as griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines,
`sulfonamides and tetracyclines might increase the photosensitivity reaction
`
`of actinic keratoses treated with LEVULAN KERASTICK Topical Solution
`(7).
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 03/2010
`
`
`
`
`
`
`
`10 OVERDOSAGE
`
`
`LEVULAN KERASTICK Overdose
`10.1
`
`
`10.2
`BLU-U Light Overdose
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`
`
`16.2
`Product Package – NDC Number
`16.3
`Storage Conditions
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are
`not listed.
`
`
`
`

`

`
`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 (PDT) Illuminator is indicated for the treatment of minimally to moderately thick
`actinic keratoses of the face or scalp.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`LEVULAN KERASTICK for 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 either scalp or face lesions, but not both
`simultaneously. The recommended treatment frequency is: one application of the LEVULAN KERASTICK
`Topical Solution and one dose of illumination per treatment site per 8-week treatment session. Each
`individual LEVULAN KERASTICK for Topical Solution should be used for only one patient. Photodynamic
`therapy for actinic keratoses with LEVULAN KERASTICK for Topical Solution is a two stage process
`involving a) application of the product to the target lesions with LEVULAN KERASTICK Topical Solution,
`followed 14 to 18 hours later by b) illumination with blue light using the BLU-U Blue Light Photodynamic
`Therapy Illuminator. The second visit, for illumination, must take place in the 14-18 hour window following
`application. Patients in clinical trials usually received application in the late afternoon, with illumination the
`following morning.
`
`
`TABLE 1 Schedule for LEVULAN KERASTICK and Blue Light Administration
`
`LEVULAN KERASTICK Topical Solution
`Time Window for Blue Light Illumination
`Application
`
`6 am
`
`7 am
`
`8 am
`
`9 am
`
`10 am
`11 am
`
`12 pm
`
`1 pm
`
`2 pm
`
`3 pm
`
`4 pm
`
`5 pm
`
`6 pm
`
`7 pm
`
`8 pm
`
`9 pm
`
`10 pm
`
`
`8 pm to Midnight
`9 pm to 1 am
`
`10 pm to 2 am
`
`11 pm to 3 am
`
`Midnight to 4 am
`1 am to 5 am
`2 am to 6 am
`3 am to 7 am
`4 am to 8 am
`5 am to 9 am
`6 am to 10 am
`
`7 am to 11 am
`
`8 am to Noon
`9 am to 1 pm
`10 am to 2 pm
`
`11 am to 3 pm
`
`Noon to 4 pm
`
`
`Treated lesions that have not completely resolved after 8 weeks may be treated a second time with
`LEVULAN KERASTICK for Topical Solution Photodynamic Therapy.
`
`
`
`

`

`Step A - LEVULAN KERASTICK for Topical Solution Application: Actinic keratoses
`
`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
`
`LEVULAN KERASTICK can be prepared either manually, or using the optional Kerastick Krusher. These
`methods are illustrated below.
`Manual Preparation:
`
`
`
`
`
`
`
`
`1. Hold the LEVULAN KERASTICK so that the
`applicator cap is pointing up.
`
`
`
`
`
`
`
`
`
`2. Crush the bottom ampule containing the solution
`vehicle by applying finger pressure to Position A
`on the cardboard sleeve.
`
`
`
`
`
`
`
`
`
`3. 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.
`
`
`
`
`
`
`
`
`
`4. Holding the LEVULAN KERASTICK between
`the thumb and forefinger, point the applicator cap
`away from the face, shake the LEVULAN
`KERASTICK gently for at least 30 Seconds to
`completely dissolve the drug powder in the
`solution vehicle. Do not press on the end cap
`while shaking.
`
`
`
`
`
`
`
`
`
`

`

`Optional Kerastick Krusher Preparation:
`
`Closed End
`
`
`
`Open End
`
`
`
`
`
`1. Open the Kerastick Krusher and properly
`position one LEVULAN KERASTICK into
`the Krusher making sure to orient the
`LEVULAN KERASTICK label “A” with the
`Krusher “A”. Firmly seat LEVULAN
`KERASTICK against the closed end of the
`Krusher (cap should be at open end).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 3. Remove the LEVULAN KERASTICK from
`
`the Krusher.
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4. Holding the LEVULAN KERASTICK between
`the thumb and forefinger, point the applicator
`cap away from the face, shake the LEVULAN
`KERASTICK gently for at least 30 Seconds to
`completely dissolve the drug powder in the
`
`solution vehicle. Do not press on the end cap
`while shaking.
`
`
`
`
`
`

`

` Application of solution
`
`Following solution admixture, remove the cap from the LEVULAN KERASTICK Topical Solution. 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. The effect of
`LEVULAN KERASTICK Topical Solution on ocular tissues is unknown. LEVULAN KERASTICK Topical
`Solution should not be applied to the periorbital area or allowed to contact ocular or mucosal surfaces. Once
`the initial application has dried, apply again in the same manner. The LEVULAN KERASTICK Topical
`Solution must be used immediately following preparation (dissolution) due to the instability of the activated
`product. If the solution application is not completed within 2 hours of activation, the applicator should be
`discarded and a new LEVULAN KERASTICK for Topical Solution used.
`Photosensitization of the treated lesions will take place over the next 14-18 hours. The actinic keratoses
`should not be washed during this time. The patient should be advised to wear a wide-brimmed hat or other
`protective apparel to shade the treated actinic keratoses from sunlight or other bright light sources until BLU­
`U treatment. The patient should be advised to reduce light exposure if the sensations of stinging and/or
`burning are experienced.
`If for any reason the patient cannot be given BLU-U treatment during the prescribed time after LEVULAN
`KERASTICK Topical Solution application, he or she may nonetheless experience sensations of stinging
`and/or burning if the photosensitized actinic keratoses are exposed to sunlight or prolonged or intense light at
`that time. The patient should be advised to wear a wide-brimmed hat or other protective apparel to shade the
`treated actinic keratoses from sunlight or other bright light sources until at least 40 hours after the application
`of LEVULAN KERASTICK Topical Solution. The patient should be advised to reduce light exposure if the
`sensations of stinging and/or burning are experienced.
`Step B - Administration of BLU-U Treatment 14 to 18 hours after application
`
`LEVULAN KERASTICK for Topical Solution is not intended for use with any device other than the BLU-U
`Blue Light Photodynamic Therapy Illuminator. Use of LEVULAN KERASTICK Topical Solution without
`subsequent BLU-U illumination is not recommended.
`At the visit for light illumination, the actinic keratoses to be treated should be gently rinsed with water and
`patted dry. Photoactivation of actinic keratoses treated with LEVULAN KERASTICK Topical Solution is
`accomplished with BLU-U illumination from the BLU-U Blue Light Photodynamic Therapy Illuminator. A
`1000 second (16 minutes 40 seconds) exposure is required to provide a 10 J/cm2 light dose. During light
`treatment, both patients and medical personnel should be provided with blue blocking protective eyewear, as
`specified in the BLU-U Operating Instructions. Please refer to the BLU-U Operating Instructions for further
`information on conducting the light treatment. Patients should be advised that transient stinging and/or
`burning at the target lesion sites occurs during the period of light exposure.
`If blue light treatment with the BLU-U Blue Light Photodynamic Therapy Illuminator is interrupted or
`stopped for any reason, it should not be restarted and the patient should be advised to protect the treated
`lesions from exposure to sunlight or prolonged or intense light for at least 40 hours after application of the
`LEVULAN KERASTICK Topical Solution.
`For patients with facial lesions:
`
`1. The BLU-U Blue Light Photodynamic Therapy Illuminator is positioned so that the base is slightly above
`the patient’s shoulder, parallel to the patient’s face.
`2. The BLU-U is positioned around the patient’s head so the entire surface area to be treated lies between 2”
`and 4” from the BLU-U surface:
`
`
`
`
`
`

`

`
`
`a) The patient’s nose should be no closer than 2” from the surface;
`b) The patient’s forehead and cheeks should be no further than 4” from the surface;
`c) The sides of the patient’s face and the patient’s ears should be no closer than 2” from the BLU-U
`
`surface.
`A Chin Rest, available from DUSA Pharmaceuticals, Inc., may be used to provide support for the patient’s
`head during treatment.
`For patients with scalp lesions:
`1. The knobs on either side of the BLU-U are loosened and the BLU-U is rotated to a horizontal position.
`2. The BLU-U is positioned around the patient’s head so the entire surface area to be treated lies between 2”
`and 4” from the BLU-U surface:
`a) The patient’s scalp should be no closer than 2” from the surface;
`b) The patient’s scalp should be no further than 4” from the surface;
`c) The sides of the patient’s face and the patient’s ears should be no closer than 2” from the BLU-U
`
`surface.
`A Chin Rest, available from DUSA Pharmaceuticals, Inc., may be used to provide support for the patient’s
`head during treatment.
`
`
`DOSAGE FORM AND STRENGTHS
`3
`Solution containing 20% aminolevulinic acid hydrochloride (ALA.HCl) by weight in a plastic applicator
`device.
`
`CONTRAINDICATIONS
`4
`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, and in patients with known
`sensitivity to any of the components of the LEVULAN KERASTICK for Topical Solution.
`
`WARNINGS AND PRECAUTIONS
`5
`5.1 Photosensitivity
`During the time period between the application of LEVULAN KERASTICK Topical Solution and exposure
`to activating light from the BLU-U Blue Light Photodynamic Therapy Illuminator, the treatment site will
`become photosensitive. After LEVULAN KERASTICK Topical Solution application, patients should avoid
`exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps,
`operating room lamps, tanning beds, or lights at close proximity) during the period prior to blue light
`treatment. Exposure may result in a stinging and/or burning sensation and may cause erythema and/or edema
`of the lesions. Before exposure to sunlight, patients should, therefore, protect treated lesions from the sun by
`wearing a wide-brimmed hat or similar head covering of light-opaque material. Sunscreens will not protect
`against photosensitivity reactions caused by visible light. It has not been determined if perspiration can spread
`the LEVULAN KERASTICK Topical Solution outside the treatment site to eye or surrounding skin.
`
`
`
`

`

`Application of LEVULAN KERASTICK Topical Solution to perilesional areas of photodamaged skin of the
`face or scalp may result in photosensitization. Upon exposure to activating light from the BLU-U Blue Light
`Photodynamic Therapy Illuminator, such photosensitized skin may produce a stinging and/or burning
`sensation and may become erythematous and/or edematous in a manner similar to that of actinic keratoses
`treated with LEVULAN KERASTICK Photodynamic Therapy. Because of the potential for skin to become
`photosensitized, the LEVULAN KERASTICK should be used by a qualified health professional to apply drug
`only to actinic keratoses and not perilesional skin.
`If for any reason the patient cannot return for blue light treatment during the prescribed period after
`application of LEVULAN KERASTICK Topical Solution (14 to 18 hours), the patient should call the doctor.
`The patient should also continue to avoid exposure of the photosensitized lesions to sunlight or prolonged or
`intense light for at least 40 hours. If stinging and/or burning is noted, exposure to light should be reduced.
`
`
`
`5.2 Irritation
`The LEVULAN KERASTICK Topical Solution contains alcohol and is intended for topical use only. Do not
`apply to the eyes or to mucous membranes. Excessive irritation may be experienced if this product is applied
`under occlusion.
`
`5.3 Coagulation Defects
`The LEVULAN KERASTICK for Topical Solution has not been tested on patients with inherited or acquired
`coagulation defects.
`
`ADVERSE REACTIONS
`6
`
`In Phase 3 studies, no non-cutaneous adverse events were found to be consistently associated with
`LEVULAN KERASTICK Topical Solution application followed by blue light exposure.
`Photodynamic Therapy Response: The constellation of transient local symptoms of stinging and/or burning,
`itching, erythema and edema as a result of LEVULAN KERASTICK Topical Solution plus BLU-U treatment
`was observed in all clinical studies of LEVULAN KERASTICK for Topical Solution Photodynamic Therapy
`for actinic keratoses treatment. Stinging and/or burning subsided between 1 minute and 24 hours after the
`BLU-U Blue Light Photodynamic Therapy Illuminator was turned off, and appeared qualitatively similar to
`that perceived by patients with erythropoietic protoporphyria upon exposure to sunlight. There was no clear
`drug dose or light dose dependent change in the incidence or severity of stinging and/or burning.
`In two Phase 3 trials, the sensation of stinging and/or burning appeared to reach a plateau at 6 minutes into the
`treatment. Severe stinging and/or burning at one or more lesions being treated was reported by at least 50% of
`the patients at some time during treatment. The majority of patients reported that all lesions treated exhibited
`at least slight stinging and/or burning. Less than 3% of patients discontinued light treatment due to stinging
`and/or burning.
`
`In the Phase 3 trials, the most common changes in lesion appearance after LEVULAN KERASTICK for
`Topical Solution Photodynamic Therapy were erythema and edema. In 99% of active treatment patients, some
`
`or all lesions were erythematous shortly after treatment, while in 79% of vehicle treatment patients, some or
`
`all lesions were erythematous. In 35% of active treatment patients, some or all lesions were edematous, while
`no vehicle-treated patients had edematous lesions. Both erythema and edema resolved to baseline or improved
`by 4 weeks after therapy. LEVULAN KERASTICK Topical Solution application to photodamaged
`perilesional skin resulted in photosensitization of photodamaged skin and in a photodynamic response (see
`Warnings and Precautions (5.2)).
`
`
`
`

`

`22%
`
`20%
`
`36%
`
`33%
`
`4%
`4%
`1%
`2%
`2%
`14%
`1%
`7%
`5%
`
`0%
`0%
`0%
`0%
`1%
`1%
`0%
`1%
`0%
`
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`
`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%
`
`Other Localized Cutaneous Adverse Experiences: Table 1 depicts the incidence and severity of cutaneous
`adverse events in Phase 3 studies, stratified by anatomic site treated.
`
`TABLE 2 Post-PDT Cutaneous Adverse Events - ALA-018/ALA-019
`SCALP
`
`FACE
`
`LEVULAN (n=139) Vehicle (n=41) LEVULAN (n=42) Vehicle (n=21)
`
`Moderate Severe Mild/ Mild/ Moderate Severe Mild/ Moderate Severe Mild/ Moderate Severe
`
`
`
`Degree of Severity
`Scaling/Crusting
`71%
`1%
`12%
`0%
`64%
`2%
`19%
`0%
`1%
`0%
`0%
`0%
`0%
`0%
`0%
`Pain
`0%
`Tenderness
`1%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`Itching
`25%
`1%
`7%
`0%
`14%
`7%
`19%
`0%
`Edema
`1%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`Ulceration
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`Bleeding/Hemorrhage
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`Hypo/hyper­
`pigmentation
`Vesiculation
`Pustules
`Oozing
`Dysesthesia
`Scabbing
`Erosion
`Excoriation
`Wheal/Flare
`Skin disorder NOS
`
`Adverse Experiences Reported by Body System: In the Phase 3 studies, 7 patients experienced a serious
`adverse event. All were deemed remotely or not related to treatment. No clinically significant patterns of
`clinical laboratory changes were observed for standard serum chemical or hematologic parameters in any of
`the controlled clinical trials.
`
`DRUG INTERACTIONS
`7
`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 griseofulvin, thiazide
`diuretics, sulfonylureas, phenothiazines, sulfonamides and tetracyclines might increase the photosensitivity
`reaction of actinic keratoses treated with LEVULAN KERASTICK for Topical Solution.
`
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`
`
`
`
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category C: Animal reproduction studies have not been conducted with aminolevulinic acid
`(ALA) HCl. It is also not known whether LEVULAN KERASTICK Topical Solution can cause fetal harm
`
`when administered to a pregnant woman or can affect reproductive capacity. LEVULAN KERASTICK for
`Topical Solution should be given to a pregnant woman only if clearly needed.
`
`

`

`
`
`8.3 Nursing Mothers
`The levels of ALA or its metabolites in the milk of subjects treated with LEVULAN KERASTICK for
`Topical Solution have not been measured. Because many drugs are excreted in human milk, caution should be
`exercised when LEVULAN KERASTICK for Topical Solution is administered to a nursing woman.
`8.4 Pediatric Use
`
`The safety and effectiveness in pediatric patients below the age of 18 have not been established.
`8.5 Geriatric Use
`Of the 243 subjects in controlled clinical trials of LEVULAN KERASTICK for Topical Solution, 64%
`(156/243) were 65 years old and over, while 23% (55/243) were 75 years old and over. No overall
`differences in safety or effectiveness were observed between these subjects and younger subjects, but greater
`sensitivity of some older individuals cannot be ruled out.
`
`10
`
`OVERDOSAGE
`
`10.1 LEVULAN KERASTICK Topical Solution Overdose
`LEVULAN KERASTICK Topical Solution overdose has not been reported. In the unlikely event that the
`drug is ingested, monitoring and supportive care are recommended. The patient should be advised to avoid
`incidental exposure to intense light sources for at least 40 hours 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:
`
`O
`
`C
`
`N H 3 + C l
`
`-
`
`C
`
`C
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`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 ALA HCl as a dry solid. The applicator tube is
`enclosed in a protective cardboard sleeve and cap. The 20% topical solution is prepared just prior to the time
`of use by breaking the ampules and mixing the contents by shaking the LEVULAN KERASTICKapplicator.
`The term “ALA HCl” refers to unformulated active ingredient, “LEVULAN KERASTICK for Topical
`Solution” refers to the drug product in its unmixed state, “LEVULAN KERASTICK Topical Solution” refers
`to the mixed drug product (in the applicator tube or after application), and “LEVULAN KERASTICK” refers
`to the applicator only.
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`12
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`CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
`Photosensitization following application of LEVULAN KERASTICK Topical Solution occurs through the
`metabolic conversion of aminolevulinic acid to protoporphyrin IX (PpIX), a photosensitizer, which
`accumulates in the skin to which LEVULAN KERASTICK Topical Solution has been applied. When
`exposed to light of appropriate wavelength and energy, the accumulated photoactive porphyrins produce a
`photodynamic reaction, resulting in a cytotoxic process dependent upon the simultaneous presence of oxygen.
`The absorption of light results in an excited state of porphyrin molecules, and subsequent spin transfer from
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`photoreactive porphyrins to molecular oxygen generates singlet oxygen, which can further react to form
`
`superoxide and hydroxyl radicals. LEVULAN KERASTICK Photodynamic Therapy of actinic keratoses is
`the combination of photosensitization by topical application of LEVULAN KERASTICK Topical Solution to
`the lesions and subsequent illumination with the BLU-U Blue Light Photodynamic Therapy Illuminator
`(BLU-U).
`
`12.2 Pharmacodynamics
`
`ALA does not exhibit fluorescence, while PpIX has a high fluorescence yield. Time-dependent changes in
`surface fluorescence have been used to determine PpIX accumulation and clearance in actinic keratoses and
`perilesional skin after application of LEVULAN KERASTICK Topical Solution in 12 patients. Peak
`fluorescence intensity was reached in 11 ± 1 hr in actinic keratoses and 12 ± 1 hr in perilesional skin. The
`mean clearance half-life of fluorescence for lesions was 30 ± 10 hr and 28 ± 6 hr for perilesional skin. The
`fluorescence in perilesional skin was similar to that in actinic keratoses. Therefore, LEVULAN
`KERASTICK Topical Solution should only be applied to the affected skin.
`
`12.3 Pharmacokinetics
`In a human pharmacokinetic study (N=6) using a 128 mg dose of sterile intravenous ALA HCl and oral ALA
`HCl (equivalent to 100 mg ALA) in which plasma ALA and PpIX were measured, the mean half-life of ALA
`was 0.70 ± 0.18 h after the oral dose and 0.83 ± 0.05 h after the intravenous dose. The oral bioavailability of
`ALA was 50-60% with a mean Cmax of 4.65 ± 0.94 µg/mL. PpIX concentrations were low and were
`detectable only in 42% of the plasma samples. PpIX concentrations in plasma were quite low relative to ALA
`plasma concentrations, and were below the level of detection (10 ng/mL) after 10 to 12 hours.
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`13
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`Nonclinical toxicology
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`No carcinogenicity testing has been carried out using ALA. No evidence of mutagenic effects was seen in
`four studies conducted with ALA to evaluate this potential. In the Salmonella-Escherichia coli/mammalian
`microsome reverse mutation assay (Ames mutagenicity assay), no increases in the number of revertants were
`observed with any of the tester strains. In the Salmonella-Escherichia coli/mammalian microsome reverse
`mutation assay in the presence of solar light radiation (Ames mutagenicity assay with light), ALA did not
`cause an increase in the number of revertants per plate of any of the tester strains in the presence or absence
`of simulated solar light. In the L5178Y TK± mouse lymphoma forward mutation assay, ALA was evaluated
`as negative with and without metabolic activation under the study conditions. PpIX formation was not
`demonstrated in any of these in vitro studies. In the in vivo mouse micronucleus assay, ALA was considered
`negative under the study exposure conditions. In contrast, at least one report in the literature has noted
`genotoxic effects in cultured rat hepatocytes after ALA exposure with PpIX formation. Other studies have
`documented oxidative DNA damage in vivo and in vitro as a result of ALA exposure.
`No assessment of effects of ALA HCl on fertility has been performed in laboratory animals. It is unknown
`what effects systemic exposure to ALA HCl might have on fertility or reproductive function.
`
`ALA-019
`LEVULAN
`
`Vehicle
`
`Clinical Studies
`14
`LEVULAN KERASTICK for Topical Solution plus blue light at 6-10.9 J/cm2, has been used to treat actinic
`keratoses in 342 patients in seven clinical trials. Phase 3 studies were two, identically designed, multicenter,
`two-arm studies using LEVULAN KERASTICK for Topical Solution plus illumination from the BLU-U for
`1000 seconds (16 min 40 sec) for a nominal exposure of 10 J/cm2. Patients were excluded from these studies
`who had a history of cutaneous photosensitization, porphyria, hypersensitivity to porphyrins,
`photodermatosis, or inherited or acquired coagulation defects. A minimum of 4 and a maximum of 15
`clinically typical, discrete, [Grade 1 (Slightly palpable actinic keratoses: better felt than seen) or Grade 2,
`(Moderately thick actinic keratoses: easily seen and felt) see Table 4 for definition], target actinic keratoses
`were identified. Target lesions on the face or on the scalp, but not in both locations in the same patient,
`received treatment. The patients were randomized to receive treatment either with the LEVULAN
`KERASTICK Topical Solution plus BLU-U or vehicle plus BLU-U. Patients were randomized at a 3 to 1
`LEVULAN to vehicle ratio. A total of 243 patients were enrolled in two Phase 3 studies (ALA-018, ALA­
`019). Lesions were designated as cleared (complete response) if the lesion had completely cleared and
`adherent scaling plaques of actinic keratoses were no longer evident on the surface of the treated skin when
`palpated. The percentage of patients in whom 75% or more of treated lesions were cleared, and the percentage
`of patients in whom 100% of treated lesions were cleared (Complete Responders), for each study at 8 weeks
`after treatment are shown in Table 3.
`TABLE 3 Patient Responses at Week 8
`ALA-018
`
`
`Vehicle
`LEVULAN
`Patients with > 75% of AK Lesions Cleared
`
`Total No. Patients
`68/87 (78%)
`6/29 (21%)
`71/93 (76%)
`
`Patients with Face
`57/71 (80%)
`2/21 (10%)
`57/67 (85%)
`Lesions
`with
`Patients
`Scalp Lesions
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`11/16 (69%)
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`4/8 (50%)
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`14/26 (54%)
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`8/32 (25%)
`7/19 (37%)
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`1/13 (8%)
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`Complete Responders
`60/87 (69%)
`49/71 (69%)
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`4/29 (14%)
`2/21 (10%)
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`59/93 (63%)
`47/67 (70%)
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`4/32 (13%)
`4/19 (21%)
`
`
`Total No. Patients
` Patients with Face
`
`Lesions
`with
`Patients
`0/13 (0%)
`12/26 (46%)
`2/8 (25%)
`11/16 (69%)
`Scalp Lesions
`Because clinical studies ALA-018 and ALA-019 had identical protocols, the combined results from the two
`trials are shown in the following tables. For actinic keratoses with a variety of thicknesses (excluding very
`thick, Grade 3 actinic keratoses which were not studied in the phase 3 trials), LEVULAN KERASTICK
`Topical Solution plus BLU-U is more effective than vehicle plus BLU-U, but as shown in Table 4, the
`percentage of lesions with complete responses at 8 weeks after treatment with LEVULAN KERASTICK
`Topical Solution plus blue light illumination was lower for those lesions that were thicker at baseline.
`Efficacy of LEVULAN KERASTICK Topical Solution plus BLU-U on higher grade lesions was not studied
`in the Phase 3 clinical efficacy trials.
`
`TABLE 4 Lesions Complete Responses at Week 8 for Different Lesion Grades
`LEVULAN
`
`Lesion Grade 1
`666/756 (88%)
`(Slightly palpable actinic keratoses: better felt than seen)
`Lesion Grade 2
`(Moderately thick actinic keratoses: easily seen and felt)
`Lesion Grade 3
`0
`0
`(Very Thick and/or hyperkeratotic actinic keratoses)
`Those patients who were not Complete Responders at week 8 had retreatment