NDA 20-965/S-003
`Page 3
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`
`
`Levulan® Kerastick®
`
`(aminolevulinic acid HCl) for Topical Solution, 20%
`
`For Topical Use Only (cid:127) 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.
`
`

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`NDA 20-965/S-003
`Page 4
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`
`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.
`
`

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`NDA 20-965/S-003
`Page 5
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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, (Grade 1 or 2,
`see table 2 for definition), 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
`Vehicle
`
`Patients with > 75% of AK Leasions 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
`Patients with
`Scalp Lesions
`
`Total No. Patients
`Patients with Face
`Lesions
`Patients with
`Scalp Lesions
`
`11/16 (69%)
`
`2/8 (25%)
`
`12/26 (46%)
`
`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 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.
`
`
`TABLE 2 Lesions Complete Responses at Week 8 for different Lesion Grades
`
`LEVULAN
`Vehicle
`Lesion Grade 1
`666/756 (88%)
`122/302 (40%)
`
`4/8 (50%)
`11/16 (69%)
`Complete Responders
`60/87 (69%)
`4/29 (14%)
`49/71 (69%)
`2/21 (10%)
`
`8/32 (25%)
`7/19 (37%)
`
`14/26 (54%)
`
`1/13 (8%)
`
`59/93 (63%)
`47/67 (70%)
`
`4/32 (13%)
`4/19 (21%)
`
`0/13 (0%)
`
`

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`NDA 20-965/S-003
`Page 6
`
`(Slightly palpable actinic
`keratoses: better felt than seen)
`Lesion Grade 2
`(Moderately thick actinic
`keratoses: easily seen and felt)
`Lesion Grade 3
`(Very Thick and/or
`hyperkeratotic actinic keratosis)
`
`495/632 (78%)
`
`52/199 (26%)
`
`0
`
`0
`
`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.
`
`

`

`NDA 20-965/S-003
`Page 7
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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 minimally to moderately
`thick actinic keratosis (Grade 1 or 2, see table 2 for definition) of the face and 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.
`
`

`

`NDA 20-965/S-003
`Page 8
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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.
`
`

`

`NDA 20-965/S-003
`Page 9
`
`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.
`
`

`

`NDA 20-965/S-003
`Page 10
`
`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.
`
`

`

`NDA 20-965/S-003
`Page 11
`
`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.
`
`

`

`NDA 20-965/S-003
`Page 12
`
`
`TABLE 5 Post-PDT Cutaneous Adverse Events - ALA-018/ALA-019
`
`FACE
`SCALP
`LEVULAN
`LEVULAN
`Vehicle (n=21)
`Vehicle (n=41)
`
`(n=42)
`(n=139)
`Moderate Severe Mild/
`Moderate Severe Mild/
`Moderate Severe Mild/
`Mild/
`Moderate Severe
`71%
`1%
`12%
`0%
`64%
`2%
`19%
`0%
`1%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`1%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`25%
`1%
`7%
`0%
`14%
`7%
`19%
`0%
`1%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`4%
`0%
`0%
`0%
`2%
`0%
`0%
`0%
`
`22%
`4%
`4%
`1%
`2%
`2%
`14%
`1%
`7%
`5%
`
`0%
`0%
`0%
`0%
`1%
`1%
`0%
`1%
`0%
`
`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%
`
`33%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`5%
`
`0%
`0%
`0%
`0%
`0%
`0%
`0%
`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
`
`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.
`
`

`

`NDA 20-965/S-003
`Page 13
`
`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.
`
`

`

`NDA 20-965/S-003
`Page 14
`
`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. NOTE: 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
`3 minutes to completely dissolve the drug
`powder in the solution vehicle.
`
`
`
`

`

`NDA 20-965/S-003
`Page 15
`
`
`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.
`
`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:
`
`

`

`NDA 20-965/S-003
`Page 16
`
`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.
`
`

`

`NDA 20-965/S-003
`Page 17
`
`
`Product Package
`Individual LEVULAN KERASTICK for Topical Solution, 20%
`Carton of 6 LEVULAN KERASTICKS for Topical Solution, 20%
`
`NDC number
`50419-810-01
`50419-810-06
`
`Storage Conditions: Store at 25°C (77°F); excursions permitted to 15 –