(aminolevulinic acid HCl) for Topical Solution, 20%
For Topical Use Only
Not for Opthalmic Use
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:
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.
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 KERASTICK 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).
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 KERASTICK 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 KERASTICK Topical Solution should only be applied to the affected skin.
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 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
|Patients with > 75% of AK Lesions Cleared|
|Total No. Patients||68/87 (78%)||6/29 (21%)||71/93 (76%)||8/32 (25%)|
|Patients with Face Lesions||57/71 (80%)||2/21 (10%)||57/67 (85%)||7/19 (37%)|
|Patients with Scalp Lesions||11/16 (69%)||4/8 (50%)||14/26 (54%)||1/13 (8%)|
|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||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 very thick, Grade 3 actinic keratoses which were not studied in the phase 3 trials), LEVULAN KERASTICK Topical Solution plus BLU-U is more effective than vehicle plus BLU-U, but as shown in Table 2, the percentage of lesions with complete responses at 8 weeks after treatment with LEVULAN KERASTICK Topical Solution plus blue light illumination was lower for those lesions that were thicker at baseline. Efficacy of LEVULAN KERASTICK Topical Solution plus BLU-U on higher grade lesions was not studied in the Phase 3 clinical efficacy trials.
TABLE 2 Lesions Complete Responses at Week 8 for Different Lesion Grades
|Lesion Grade 1|
(Slightly palpable actinic keratoses: better felt than seen)
|666/756 (88%)||122/302 (40%)|
|Lesion Grade 2|
(Moderately thick actinic keratoses: easily seen and felt)
|495/632 (78%)||52/199 (26%)|
|Lesion Grade 3|
(Very Thick and/or hyperkeratotic actinic keratoses)
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||24/56 (43%)||2/49 (4%)|
|Patients with Face Lesions||21/40 (53%)||2/31 (6%)|
|Patients with Scalp Lesions||3/16 (19%)||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
|Patients with > 75% 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%)|
|Total No. Patients||129/180 (72%)||7/61 (11%)|
|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.
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