CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER: 20-965
`
`FINAL PRINTED LABELING
`
`

`

`LEVULANQKERASTICK" (aminolevulinic acid HCI) for Topical Solution, 20%
`For Topical Use Only
`Not for Ophthalmic Use
`
`DESCRIPTION
`
`LEVULAN” KERASTlCK" (aminolevulinic acid HCI) for Topical Solution, 20%, contains
`the hydrochloride salt of 5—aminolevulinic acid (ALA), an endogenous 5-carbon
`aminoketone.
`
`Aminolevulinic acid HCI (ALA HCI) 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 HCI is 5—amino—4-oxopentanoic acid hydrochloride (MW =
`167.59). The structural formula is represented below:
`
`o
`
`my Cl'
`
`OH
`
`The LEVULAN" KERASTlCK" 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 HCI 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 KERASTlCK applicator. The term "ALA HCI” refers to
`unformulated active ingredient, “LEVULAN KERASTlCK for Topical Solution” refers to
`the drug product in its unmixed state, “LEVULAN KERASTlCK Topical Solution" refers
`to the mixed drug product (in the applicator tube or after application), and “LEVULAN
`KERASTlCK” refers to the applicator only.
`
`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 protopcr; thyrin lX (PplX), 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 PplX, 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 PplX, which accumulates in the skin to which LEVULAN Topical Solution has
`been applied. When exposed to light of appropriate wavelength and energy,
`the
`accumulated PplX 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 PplX 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-UW‘ Blue Light Photodynamic
`Therapy llluminator (BLU-U), is the basis for LEVULAN photodynamic therapy (PDT).
`
`In a human pharmacokinetic study (N=6) using a 128 mg dose of
`Pharmacokinetics:
`sterile intravenous ALA HCI 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 i: 0.05 h after the intravenous dose. The oral bioavailability of
`ALA was 50-60% with a mean Cmax of 4.65 i 0.94 uglmL. PplX 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 nglmL) after 10 to 12 hours.
`
`ALA does not exhibit fluorescence, while PplX has a high fluorescence yield. Time-
`dependent changes in surface fluorescence have been used to determine PplX
`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 i 1 h in actinic keratoses and 12 i 1 h in perilesional skin.
`.The
`mean clearance half-life of fluorescence for lesions was 30 d: 10 h and 28 :t 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.
`
`Clinical Studies: LEVULAN KERASTICK for Topical Solution, 20%, plus blue light at 6-
`10.9 J/cmz, 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 KERASTICKfor Topical Solution applicators plus illumination from the BLU-U
`for 1000 seconds (16 min 40 sec) for a nominal exposure of 10 chm2. Patients were
`excluded from these studies who had a history of cutaneous photosensitization,
`porphyria, hypersensitivity to porphyrins, photoderrnatosis, 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-018
`
`ALA-019
`
`LEVU LAN
`
`Vehicle
`
`LEVULAN
`
`Vehicle
`
`Patients with 275% of AK Lesions Cleared
`
`Total No. Patients
`
`68/87 (78%)
`
`6/29 (21%)
`
`71/93 (76%)
`
`8/32 (25%)
`
`Patients with Face
`
`57/71 (80%)
`
`2/21 (10%)
`
`57/67 (85%)
`
`7/19 (37%)
`
`Lesions
`
`Patients with Scalp
`
`11/16 (69%)
`
`4/8 (50%)
`
`14/26 (54%)
`
`1/13 (8%)
`
`Lesions
`
`Complete Responders
`
`Total No. Patients
`
`60/87 (69%)
`
`4/29(14%)
`
`59/93 (63%)
`
`4/32 (13%)
`
`Patients with Face
`Lesions
`
`49/71 (69%)
`
`2/21 (10%)
`
`47/67 (70%)
`
`4/19 (21%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patients with Scalp
`
`
`Lesions
`
`1 1/16 (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 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. Lesion Complete Responses at Week 8 for
`Different Lesion Grades
`__—
`
`
`
`Lesion Grade 1
`666/756 (88%)
`122/302 (40%)
`(slightly palpable
`
`actinic keratoses:
`better felt than seen
`
`
`
`
`Lesion Grade 2
`
`495/632 (78%)
`52/199 (26%)
`
`(moderately thick
`
`
`actinic keratoses:
`
`
`easily seen and felt)
`
`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 Receivino Two Treatments
`__-
`
`
`
`
`
`
`
`
`
`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.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`

`

`Table 4. Patient Responses at Week 12, among Patients who
`
`Received One or Two Treatments
`
`LEVULAN
`
`Vehicle
`
`Patients with 275% of AK Lesions Cleared
`
`
`
`Total No. Patients
`
`158/180 (88%)
`
`12/61 (20%)
`
`Patients with Face Lesions
`
`127/138 (92%)
`
`8/40 (20%)
`
`Patients with Scalp Lesions
`
`31/42 (74%)
`
`4/21 (19%)
`
`Complete Responders
`
`Total No. Patients
`
`129/180 (72%)
`
`7/61 (1 1%)
`
`Patients with Face Lesions
`
`108/138 (78%)
`
`5/40 (13%)
`
`Patients with Scalp Lesions
`
`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.
`
`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.
`
`APPEARS THIS WAY
`
`OE CWGWAL
`
`

`

`u. u:
`
`A
`Ink-Ind .-
`W :-
`uvuum
`was.
`H.101
`nu:
`trail/x
`\N‘rfiu
`uvuuNIIsI-t
`Week 0 W
`
`unto
`/\
`No date
`3:117 “:50
`
`I'M
`“NM
`#1:;
`
`9
`W Ck 8
`
`.
`
`3:00
`
`:21?"
`
`Clan/\Nodur
`
`and
`
`":36 Week 12
`
`yu\
`Ian-u
`Clo-r Medan—9 VW
`“I.
`"-52
`N."
`
`/\ Out
`
`It's A?!" us:
`
`u. ch-
`
`":49
`
`INDICATIONS AND USAGE
`
`The LEVULAN KERASTICK for Topical Solution plus blue light illumiration using the
`BLU-U Blue Light Photodynamic Therapy llluminator 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 llluminator 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.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`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.
`
`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 llluminator, 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.
`
`lnforrnation for Patients:
`
`LEVULAN Photodynamic Therapy for Actinic Keratoses
`
`for actinic
`The first step in LEVULAN KERASTICK photodynamic therapy (PDT)
`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.
`
`Photosensitiviy
`
`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 mt 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 burring is noted, exposure to light should be reduced.
`
`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
`coIi/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 coIi/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 fonivard mutation assay, ALA was evaluated as negative with and without
`metabolic activation under the study conditions. PplX 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 PplX 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 HCI on fertility has been performed in laboratory
`animals.
`It is unknown what effects systemic exposure to ALA HCI might have on
`fertility or reproductive function.
`
`Pregnancy Category (2 Animal reproduction studies have not been conducted with
`ALA HCI.
`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.
`
`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 llluminator 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 burring.
`
`

`

`In the 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 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.
`
`
`
` Table 5. Post-PDT Cutaneous Adverse Events — ALA-018/ALA-019
` _ FACE SON-P
`
`
`—_-I-——-—-
`
`Save '
`
`Moderate
`
`Moderate
`
`Moderate
`
`Moderate
`
`II-“mmnmn
`
`Crustin-
`
`
`
`. i - mentation
`
`NOS
`
`m-mum-m-m-mm-
`“MIR-“mm.“
`“MIR-“IE.“
`mmmmmmm
`—lE-IE-IE-m-IZ-mm-Ifi_
`mum-Elm“
`Hemorrha-e
`n
`u-“mw
`“mm-“mam“
`mun-mm—mm-m-m
`[m-lmmmz-m-lm-m-m-m
`mummmmmmm
`mmmmmmmmm
`m—mmmmmmm
`mwmmmmm
`mmmmmmm
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“m “mum“
`
`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
`
`10
`
`

`

`treatment. No clinically significant patterns of clinical IabOratory 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 llluminator following LEVULAN KERASTICK
`Topical Solution application.
`
`DOSAGE AND ADMINISTRATION
`
`LEVULAN KERASTICK for Topical Solution is intended for direct application to
`individual lesions diagnosed as actinic keratoses and n_ot 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 llluminator. 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
`
`Time Window for Blue Light
`Illumination
`
`
`
`.
`
`
`
`
`
`
`
`Midnight to 4am
`
`LEVULAN
`KERASTICK Topical
`Solution Application
`@- 8pm to midnight
`9pm to 1am
`_ 109m to 2am
`1 1pm to 3am
`
`
`
`
`11
`
`

`

`11am
`
`A'o
`
`s: ‘U3
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`Step A - LEVULAN KERASTICK for Topical Solution Application: Actinic keratoses
`targeted for treatment should be clean and dry prior to application of LEVULAN
`KERASTICK Topical Solution.
`"
`
`Preparation:
`
`The LEVULAN KERASTICK Topical Solution should be prepared as follows:
`
`APPEARS THIS WAY
`0N 0R|G|NAL
`
`12
`
`

`

`BEST POSSIBLE COPY
`
`(1)
`
`Hold the LEVULAN KERASTICK so that the
`applicator cap is pointing up.
`
`Crush the bottom ampule containing the
`solution vehicle by applying finger pressure
`to Position A on the cardboard sleeve.
`
`drug powder in the solution vehicle.
`
`(2)
`
`(3)
`
`_,__,e_ew 7
`
`(4)
`
`Crush the top ampule containing the ALA
`HCI powder by applying finger pressure to
`Position B on the
`cardboard sleeve.
`
`Continue crushing the applicator downward,
`applying finger pressure to Position A. ,
`
`KERASTICK
`LEVULAN
`the
`Holding
`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
`
`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.
`
`13
`
`

`

`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
`WVAnonetheless experience sensations of stinging and/or bum’ng 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 8 - Administration of BLU-U Treatment 14 to 18 hours after application of.
`LEVULAN KERASTICK Topical Solution: At the visit for light ilumination, 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 llluminator. A 1000 second (16 minutes 40 seconds) exposure
`is required to provide a 10 chm2 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.
`
`lf blue light treatment with the BLU-U Blue Light Photodynamic Therapy llluminator 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
`
`14
`
`

`

`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 llluminator 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,
`support for the patient’s head during treatment.
`
`Inc., may be used to provide
`
`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
`
`Ax”-.- rhorizontal‘posilion.
`
`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,
`support for the patient's head during treatment.
`
`Inc., may be used to provide
`
`LEVULAN KERASTICK for Topical Solution is not intended for use with any
`device other than the BLU-U Blue Light Photodynamic llluminator. 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 single-unit dosage form,
`supplied in packs of 4, 6 or 12. Each LEVULAN KERASTICK for Topical Solution
`applicator consists of a plastic tube containing two sealed glass ampules and an
`
`15
`
`

`

`applicator tip. One ampule contains 1.5 mL of solution vehicle. The other ampule
`contains 354 mg of aminolevulinic acid HCI. The applicator is covered with a protective
`cardboard sleeve and cap.
`
`NDC number
`Product Package
`Carton of 4 LEVULANO KERASTICKS” for Topical Solution, 20% xxxxx-xx-xxx
`Carton of 6 LEVULAN” KERASTICKSm1for Topical Solution, 20% xxxxx-xx-xxx
`Carton of 12 LEVULAN® KERASTICKS for Topical Solution, 20% xxxxx-xx-xxx
`
`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.
`
`[RX SYMBOL]
`
`LEVULAN® is.a registered trademark of DUSA Pharmaceuticals, Inc.
`KERASTICK is a trademark of DUSA Pharmaceuticals, Inc.
`w—"*‘BLU-Um is a trademark of DUSA PharmaceutiCals, inc.
`
`Manufactured by:
`
`North Safety Products
`Cranston, RI 02921
`
`Manufactured for.
`
`DUSA Pharmaceuticals, Inc.
`Wilmington, MA 01887
`
`Revision:
`
`December 3, 1999.
`
`APPEARS THIS WAY
`0" ORIGINAL
`
`16
`
`

`

`PHOTODYNAMIC THERAPY (PDT)
`Using
`the LEVULAN” KERASTlCKT" for Topical Solution, 20%
`(generic name = aminolevulinic acid HCl)
`4.
`the Bl.U-UWl Blue Light Photodynamic Therapy llluminator
`for Topical Use on the Face and Scalp
`
`What is LEVULAN" KEFtASTICKTM for Topical Solution + Blue Light PDT?
`
`This is a two-step (drug + blue light) treatment designed to treat actinic keratosis
`(AK) lesions on the face or scalp. AKs are precancerous skin changes caused
`by chronic sun exposure.
`If untreated, AKs may develop into skin cancer.
`
`In the first pan of the treatment, your doctor or other health care provider applies
`LEVULAN KERASTICK Topical Solution. using the LEVULAN KERASTICK
`Topical Solution applicator, to individual AK lesions of the face