`
`(aminolevulinic acid HCl) for Topical Solution, 20%
`
`For Topical Use Only • Not for Ophthalmic Use
`
`DESCRIPTION
`
`LEVULAN® KERASTICK® (aminolevulinic acid HCl) for Topical Solution, 20%,
`contains the hydrochloride salt of aminolevulinic acid (ALA), an endogenous 5-carbon
`aminoketone.
`
`Aminolevulinic acid HCl (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
`
`C
`
`O
`
`C
`
`O H
`
`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 KERASTICK applicator. 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.
`
`For Text Only Page 1 of 15
`
`
`
`CLINICAL PHARMACOLOGY
`
`Pharmacology: The metabolism of aminolevulinic acid (ALA) is the first step in the
`biochemical pathway resulting in heme synthesis. Aminolevulinic acid is not a
`photosensitizer, but rather a metabolic precursor of protoporphyrin IX (PpIX), which is a
`photosensitizer. The synthesis of ALA is normally tightly controlled by feedback
`inhibition of the enzyme, ALA synthetase, presumably by intracellular heme levels.
`ALA, when provided to the cell, bypasses this control point and results in the
`accumulation of PpIX, which is converted into heme by ferrochelatase through the
`addition of iron to the PpIX nucleus.
`
`According to the presumed mechanism of action, photosensitization following
`application of LEVULAN Topical Solution occurs through the metabolic conversion of
`ALA to PpIX, which accumulates in the skin to which LEVULAN Topical Solution has
`been applied. When exposed to light of appropriate wavelength and energy, the
`accumulated PpIX produces a photodynamic reaction, a cytotoxic process dependent
`upon the simultaneous presence of light and oxygen. The absorption of light results in an
`excited state of the porphyrin molecule, and subsequent spin transfer from PpIX to
`molecular oxygen generates singlet oxygen, which can further react to form superoxide
`and hydroxyl radicals. Photosensitization of actinic (solar) keratosis lesions using the
`LEVULAN KERASTICK, plus illumination with the BLU-U™ Blue Light
`Photodynamic Therapy Illuminator (BLU-U), is the basis for LEVULAN photodynamic
`therapy (PDT).
`
`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.
`
`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 keratosis lesions and perilesional skin after
`application of LEVULAN Topical Solution in 12 patients. Peak fluorescence intensity
`was reached in 11 ± 1 h in actinic keratoses and 12 ± 1 h in perilesional skin. The mean
`clearance half-life of fluorescence for lesions was 30 ± 10 h and 28 ± 6 h for perilesional
`skin. The fluorescence in perilesional skin was similar to that in actinic keratoses.
`Therefore, LEVULAN Topical Solution should only be applied to the affected skin.
`
`For Text Only Page 2 of 15
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`
`
`Clinical Studies: LEVULAN KERASTICK for Topical Solution, 20%, plus blue light at
`6-10.9 J/cm2, has been used to treat actinic keratoses in 232 patients in six clinical trials.
`Phase 3 studies were two, identically designed, multicenter, two-arm studies using
`LEVULAN KERASTICK for Topical Solution applicators 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,
`non-hyperkeratotic, target actinic keratosis lesions 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
`for 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 1.
`TABLE 1 Patient Responses at Week 8
`ALA-019
`ALA-018
`LEVULAN
`Vehicle
`LEVULAN
`Patients with > 75% of AK Leasions Cleared
`68/87 (78%)
`6/29 (21%)
`71/93 (76%)
`
`Vehicle
`
`8/32 (25%)
`
`Total No. Patients
`Patients with Face
`Lesions
`Patients with
`Scalp Lesions
`
`Total No. Patients
`Patients with Face
`Lesions
`Patients with
`Scalp Lesions
`
`57/71 (80%)
`
`2/21 (10%)
`
`57/67 (85%)
`
`7/19 (37%)
`
`11/16 (69%)
`
`4/8 (50%)
`
`14/26 (54%)
`
`1/13 (8%)
`
`Complete Responders
`60/87 (69%)
`4/29 (14%)
`
`59/93 (63%)
`
`4/32 (13%)
`
`49/71 (69%)
`
`2/21 (10%)
`
`47/67 (70%)
`
`4/19 (21%)
`
`11/16 (69%)
`
`2/8 (25%)
`
`12/26 (46%)
`
`0/13 (0%)
`
`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 hyperkeratotic actinic keratoses), LEVULAN
`KERASTICK for Topical Solution plus BLU-U is more effective than vehicle plus BLU-
`U, but as shown in Table 2, the percentage of lesions with complete responses at 8 weeks
`after treatment with LEVULAN KERASTICK for Topical Solution plus blue light
`illumination was lower for those lesions that were thicker at baseline. Efficacy of
`LEVULAN KERASTICK for Topical Solution plus BLU-U on higher grade lesions was
`not studied in the Phase 3 clinical efficacy trials.
`
`For Text Only Page 3 of 15
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`
`
`TABLE 2 Lesions Complete Responses at Week 8 for Different Lesion Grades
`LEVULAN
`Vehicle
`
`Lesion Grade 1
`(Slightly palpable actinic
`keratoses: better felt than seen)
`Lesion Grade 2
`(Moderately thick actinic
`keratoses: easily seen and felt)
`
`666/756 (88%)
`
`122/302 (40%)
`
`495/632 (78%)
`
`52/199 (26%)
`
`Those patients who were not Complete Responders at week 8 had retreatment of the
`persistent target lesions at week 8. Among the patients undergoing retreatment, efficacy
`results seen at 12 weeks after the initial treatment, i.e., at 4 weeks after the second
`treatment, are shown in Table 3.
`TABLE 3 Complete Responders at Week 12, among Patients Receiving Two
`Treatments
`
`Total No. Patients
`Patients with Face Lesions
`Patients with Scalp Lesions
`
`LEVULAN
`24/56 (43%)
`21/40 (53%)
`3/16 (19%)
`
`Vehicle
`2/49 (4%)
`2/31 (6%)
`0/18 (0%)
`
`The efficacy results seen at 12 weeks after treatment, which include the results at 12
`weeks for those patients who received a single treatment as well as the results at 12 weeks
`for those patients who received a second treatment at week 8, are shown in Table 4.
`TABLE 4 Patient Responses at Week 12, among Patients who Received One or Two
`Treatments
`
`Total No. Patients
`Patients with Face Lesions
`Patients with Scalp Lesions
`
`Total No. Patients
`Patients with Face Lesions
`Patients with Scalp Lesions
`
`Vehicle
`LEVULAN
`Patients with > 75% of AK Leasions Cleared
`158/180 (88%)
`12/61 (20%)
`127/138 (92%)
`8/40 (20%)
`31/42 (74%)
`4/21 (19%)
`Complete Responders
`129/180 (72%)
`7/61 (11%)
`108/138 (78%)
`5/40 (13%)
`21/42 (50%)
`2/21 (10%)
`
`Among Complete Responders at week 8, 93% (in study ALA-018) and 83% (in study
`ALA-019) maintained complete response at week 12. Among patients with scalp lesions,
`the percentage of patients with 100% of AK lesions having complete response declined
`from week 8 (55%) to week 12 (50%), because there were more patients with scalp
`lesions with 100% of AK lesions cleared at week 8 who had a recurrence of a lesion by
`week 12 than there were patients with scalp lesions who had retreatment of persistent
`lesions at week 8 and who then achieved 100% of AK lesions cleared by week 12.
`Patients did not receive follow-up past 12 weeks after the initial treatment.
`
`For Text Only Page 4 of 15
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`
`
`Patient outcomes recorded in the two Phase 3 trials are depicted in the following
`flowchart, in which Complete Responders are designated clear. Seven patients in the
`active treatment arm and three patients in the vehicle treatment arm withdrew or were lost
`to follow-up, and their outcomes are not included in the flowchart. Three patients in the
`active treatment arm were treated at baseline but did not return for evaluation until week
`12. One patient in the active treatment arm and two in the vehicle treatment arm who
`were not clear at week 8 did not receive retreatment.
`
`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
`non-hyperkeratotic actinic keratoses of the face or scalp.
`
`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, porphyria or known allergies
`to porphyrins, and in patients with known sensitivity to any of the components of the
`LEVULAN KERASTICK for Topical Solution.
`
`For Text Only Page 5 of 15
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`
`
`WARNINGS
`
`The LEVULAN KERASTICK for 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.
`
`PRECAUTIONS
`
`General: 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 PDT. Because of the potential for skin to become photosensitized, 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.
`
`The LEVULAN KERASTICK for Topical Solution has not been tested on patients with
`inherited or acquired coagulation defects.
`
`For Text Only Page 6 of 15
`
`
`
`Information for Patients:
`
`LEVULAN Photodynamic Therapy for Actinic Keratoses.
`
`The first step in LEVULAN KERASTICK photodynamic therapy (PDT) for actinic
`keratoses is application of the LEVULAN KERASTICK for Topical Solution to actinic
`keratoses located on the patient’s face or scalp. After LEVULAN KERASTICK for
`Topical Solution is applied to the actinic keratoses in the doctor’s office, the patient will
`be told to return the next day. During this time the actinic keratoses will become sensitive
`to light (photosensitive). Care should be taken to keep the treated actinic keratoses dry
`and out of bright light. After LEVULAN KERASTICK Topical Solution is applied, it is
`important for the patient to wear light-protective clothing, such as a wide-brimmed hat,
`when exposed to sunlight or sources of light. Fourteen to eighteen hours after application
`of LEVULAN KERASTICK Topical Solution the patient will return to the doctor’s
`office to receive blue light treatment, which is the second and final step in the treatment.
`Prior to blue light treatment, the actinic keratoses will be rinsed with tap water. The
`patient will be given goggles to wear as eye protection during the blue light treatment.
`The blue light is of low intensity and will not heat the skin. However, during the light
`treatment, which lasts for approximately 17 minutes, the patient will experience
`sensations of tingling, stinging, prickling or burning of the treated lesions. These feelings
`of discomfort should improve at the end of the light treatment. Following treatment, the
`actinic keratoses and, to some degree, the surrounding skin, will redden, and swelling and
`scaling may also occur. However, these lesion changes are temporary and should
`completely resolve by 4 weeks after treatment.
`
`Photosensitivity
`
`After LEVULAN KERASTICK Topical Solution is applied to the actinic keratoses in the
`doctor’s office, the patient should avoid exposure of the photosensitive actinic keratoses
`to sunlight or bright indoor light (e.g., from examination lamps, operating room lamps,
`tanning beds, or lights at close proximity) during the period prior to blue light treatment.
`If the patient feels stinging and/or burning on the actinic keratoses, exposure to light
`should be reduced. Before going into sunlight, the patient should protect treated lesions
`from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque
`material. Sunscreens will not protect the patient against photosensitivity reactions.
`
`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.
`
`For Text Only Page 7 of 15
`
`
`
`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 the LEVULAN
`KERASTICK for Topical Solution.
`
`Carcinogenesis, Mutagenesis, Impairment to 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.
`
`Pregnancy Category C: Animal reproduction studies have not been conducted with
`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 Topical Solution should be given to a pregnant
`woman only if clearly needed.
`
`Nursing Mothers: The levels of ALA or its metabolites in the milk of subjects treated
`with LEVULAN KERASTICK Topical Solution have not been measured. Because many
`drugs are excreted in human milk, caution should be exercised when LEVULAN
`KERASTICK Topical Solution is administered to a nursing woman.
`
`ADVERSE REACTIONS
`
`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.
`
`For Text Only Page 8 of 15
`
`
`
`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.
`
`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 Precautions).
`
`Other Localized Cutaneous Adverse Experiences: Table 5 depicts the incidence and
`severity of cutaneous adverse events, stratified by anatomic site treated.
`
`For Text Only Page 9 of 15
`
`
`
`TABLE 5 Post-PDT Cutaneous Adverse Events - ALA-018/ALA-019
`FACE
`SCALP
`LEVULAN
`LEVULAN
`(n=139)
`(n=42)
`Mild/
`Mild/
`Moderate
`Moderate
`71%
`64%
`1%
`0%
`1%
`2%
`25%
`14%
`1%
`0%
`4%
`2%
`
`Degree of Severity
`
`Severe
`
`1%
`0%
`0%
`1%
`0%
`0%
`
`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 (n=41)
`
`Vehicle (n=21)
`
`Mild/
`Moderate
`12%
`0%
`0%
`7%
`0%
`0%
`
`Severe
`
`Severe
`
`0%
`0%
`0%
`0%
`0%
`0%
`
`2%
`0%
`0%
`7%
`0%
`0%
`
`Severe
`
`Mild/
`Moderate
`19%
`0%
`0%
`19%
`0%
`0%
`
`0%
`0%
`0%
`0%
`0%
`0%
`
`0%
`
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`
`0%
`
`4%
`
`0%
`
`0%
`
`0%
`
`2%
`
`0%
`
`0%
`
`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%
`
`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.
`
`OVERDOSAGE
`
`LEVULAN KERASTICK Topical Solution Overdose: LEVULAN KERASTICK
`Topical Solution overdose have 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. The
`consequences of exceeding the recommended topical dosage are unknown.
`
`BLU-U Light Overdose: There is no information on overdose of blue light from the
`BLU-U Blue Light Photodynamic Therapy Illuminator following LEVULAN
`KERASTICK Topical Solution application.
`
`For Text Only Page 10 of 15
`
`
`
`DOSAGE AND ADMINISTRATION
`
`LEVULAN KERASTICK for Topical Solution 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 Topical Solution
`and one dose of illumination per treatment site per 8-week treatment session. Each
`individual LEVULAN KERASTICK 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, 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 6 Schedule for LEVULAN and Blue Light Administration
`LEVULAN KERASTICK
`Time Window for
`Topical Solution Application
`Blue Light Illumination
`6 am
`8 pm to Midnight
`7 am
`9 pm to 1 am
`8 am
`10 pm to 2 am
`9 am
`11 pm to 3 am
`10 am
`Midnight to 4 am
`11 am
`1 am to 5 am
`12 pm
`2 am to 6 am
`1 pm
`3 am to 7 am
`2 pm
`4 am to 8 am
`3 pm
`5 am to 9 am
`4 pm
`6 am to 10 am
`5 pm
`7 am to 11 am
`6 pm
`8 am to Noon
`7 pm
`9 am to 1 pm
`8 pm
`10 am to 2 pm
`9 pm
`11 am to 3 pm
`10 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.
`Patients did not receive follow-up past 12 weeks after the initial treatment, so the
`incidence of recurrence of treated lesions past 12 weeks and the role of further treatment
`is not known.
`
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`
`
`Step A - LEVULAN KERASTICK for Topical Solution Application: Actinic
`keratoses targeted for treatment should be clean and dry prior to application of
`LEVULAN KERASTICK for Topical Solution.
`
`Preparation:
`
`The LEVULAN KERASTICK Topical Solution should be prepared as follows:
`
`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. 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
`3 minutes to completely dissolve the drug
`powder in the solution vehicle.
`
`For Text Only Page 12 of 15
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`
`
`LEVULAN KERASTICK Preparation: Following solution admixture, remove the cap
`from the LEVULAN KERASTICK. The dry applicator tip should be dabbed on a gauze
`pad until uniformly wet with solution.
`
`Application:
`
`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 keratosis
`lesions 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 keratosis lesions 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 of
`LEVULAN KERASTICK Topical Solution: 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, to minimize ocular exposure. 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.
`
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`
`
`
`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 from the first visit.
`
`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.
`
`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 for Topical Solution without subsequent BLU-U
`illumination is not recommended.
`
`HOW SUPPLIED
`
`The LEVULAN KERASTICK for Topical Solution, 20%, is a singleunit dosage form,
`supplied in packs of 6. Each LEVULAN KERASTICK for Topical Solution 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 354 mg of
`aminolevulinic acid HCl. The applicator is covered with a protective cardboard sleeve
`and cap.
`
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`
`
`
`NDC number
`Product Package
`50419-810-01
`Individual LEVULAN KERASTICK for Topical Solution, 20%
`Carton of 6 LEVULAN KERASTICKS for Topical Solution, 20% 50419-810-06
`
`Storage Conditions: Store at 25°C (77°F); excursions permitted to 15 – 30°C (59° –
`86°F). The LEVULAN KERASTICK for Topical Solution should be used immediately
`following preparation (dissolution). Solution application must be completed within 2
`hours of preparation. An applicator that has been prepared must be discarded 2 hours
`after mixing (dissolving) and a new LEVULAN KERASTICK for Topical Solution used,
`if needed.
`
`LEVULAN® is a registered trademark of DUSA Pharmaceuticals, Inc.
`KERASTICK® is a registered trademark of DUSA Pharmaceuticals, Inc.
`BLU-U® is a registered trademark of DUSA Pharmaceuticals, Inc.
`
`Manufactured by:
`
`Manufactured for:
`
`Distributed by:
`
`North Safety Products
`Cranston, RI 02921
`
`DUSA Pharmaceuticals, Inc.
`Wilmington, MA 01887
`
`Berlex Laboratories
`Wayne, NJ 07470
`
`Revision: March 1, 2002
`
`605810
`
`For more information please contact:
`
`1-888-BERLEX4 (237-5394)
`www.berlex.com
`
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`