Levulan Drug Information
Generic name: AMINOLEVULINIC ACID HYDROCHLORIDE
Uses of Levulan
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 keratoses of the face, scalp, or upper extremities. LEVULAN KERASTICK for topical solution, a porphyrin precursor, plus blue light illumination using the BLU-U Blue Light Photodynamic Therapy Illuminator is indicated for photodynamic therapy (treatment) of minimally to moderately thick actinic keratoses of the face or scalp, or actinic keratoses of the upper extremities.
Dosage & Administration of Levulan
| 1The incubation time is 14-18 hours for actinic keratosis lesions on the face or scalp. 2 The incubation time is 3 hours for actinic keratosis lesions on the upper extremities. | |
|---|---|
| 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 |
Side Effects of Levulan
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rate observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, no non-cutaneous adverse events were found to be consistently associated with LEVULAN KERASTICK photodynamic therapy. Photodynamic Therapy Response: The constellation of transient local symptoms of stinging and/or burning, itching, erythema and edema as a result of LEVULAN KERASTICK photodynamic therapy (PDT) was observed in all clinical trials 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. Local skin reactions at the application site were observed in 99% of subjects treated with LEVULAN KERASTICK topical solution and BLU-U Blue Light Photodynamic Therapy Illuminator.
The most common local adverse reactions (incidence ≥ 10%) were application site stinging/burning, erythema, edema, scaling/crusting, hypo/hyperpigmentation, itching, erosion, oozing/vesiculation/crusting, dryness. In the trials for face and scalp lesions, severe stinging and/or burning at one or more lesions during light treatment was reported by at least 50% of subjects. Severe stinging and/or burning also occurred during light treatment in 9% of subjects receiving treatment for upper extremity lesions.
The majority of subjects reported that all lesions treated exhibited at least slight stinging and/or burning. In trials of the face and scalp, the sensation of stinging/burning appeared to reach a plateau at 6 minutes into the treatment. Less than 3% of subjects receiving treatment for face or scalp lesions discontinued light treatment because of stinging/burning.
No subjects discontinued light treatment in the trial for upper extremity lesions. In trials for the face or scalp lesions, 99% of the active treatment group and 79% of the vehicle group experienced erythema shortly after treatment. In the trial for the upper extremity lesions, 99% of LEVULAN KERASTICK topical solution treatment group and 52% of the vehicle group experienced erythema on visit Days 2-3. Approximately 35% of LEVULAN KERASTICK topical solution group had edema, while edema occurred in < 1% of the vehicle group.
Both erythema and edema resolved to baseline or improved by 4 weeks after therapy for face or scalp. Edema resolved by 4 weeks and erythema resolved to baseline by 8 weeks for upper extremities. The application of LEVULAN KERASTICK topical solution to perilesional skin resulted in stinging, burning, erythema and edema similar to treated actinic keratoses . Other Localized Cutaneous Adverse Experiences: Table 2 depicts the incidence and severity of cutaneous adverse events in trials for the face and scalp.
TABLE 2 Post-PDT Cutaneous Adverse Events – ALA-018/ALA-019 For the Face and Scalp FACE SCALP LEVULAN KERASTICK Topical Solution + PDT (n=139) Vehicle + PDT (n=41) LEVULAN KERASTICK Topical Solution + PDT (n=42) Vehicle + PDT (n=21) Degree of Severity Mild/ Moderate Severe Mild/ Moderate Severe Mild/ Moderate Severe Mild/ Moderate Severe Scaling/Crusting 71% 1% 12% 0% 64% 2% 19% 0% Pain 1% 0% 0% 0% 0% 0% 0% 0% Tenderness 1% 0% 0% 0% 2% 0% 0% 0% Itching 25% 1% 7% 0% 14% 7% 19% 0% Edema 1% 0% 0% 0% 0% 0% 0% 0% Ulceration 4% 0% 0% 0% 2% 0% 0% 0% Bleeding/Hemorrhage 4% 0% 0% 0% 2% 0% 0% 0% Hypo/hyper-pigmentation 22% 20% 36% 33% Vesiculation 4% 0% 0% 0% 5% 0% 0% 0% Pustules 4% 0% 0% 0% 0% 0% 0% 0% Oozing 1% 0% 0% 0% 0% 0% 0% 0% Dysesthesia 2% 0% 0% 0% 0% 0% 0% 0% Scabbing 2% 1% 0% 0% 0% 0% 0% 0% Erosion 14% 1% 0% 0% 2% 0% 0% 0% Excoriation 1% 0% 0% 0% 0% 0% 0% 0% Wheal/Flare 7% 1% 0% 0% 2% 0% 0% 0% Skin disorder NOS 5% 0% 0% 0% 12% 0% 5% 0% Table 3 depicts the incidence of other cutaneous adverse events in Phase 3 studies for the upper extremities. TABLE 3 Percentage of Subjects with Cutaneous Adverse Reactions by the Most Severe Grade Reported Post-Baseline – CP0108 For Upper Extremities LEVULAN KERASTICK Topical Solution + PDT (N=135) Vehicle + PDT (N=134) Degree of Severity Minimal/ Mild Moderate/ Severe Total Minimal/ Mild Moderate/ Severe Total Edema 51% 4% 56% 7% 1% 8% Erythema 35% 65% 100% 63% 12% 75% Hyper-pigmentation 64% 9% 73% 57% 10% 66% Hypo-pigmentation 46% 4% 50% 50% 5% 55% Oozing/Vesiculation/ Crusting 36% 5% 41% 8% 2% 10% Scaling and Dryness 65% 22% 87% 58% 7% 64% Stinging/Burning 23% 73% 96% 23% 0% 23% In the trial for upper extremity lesions, itching and scabbing occurred in 8% and 4%, respectively, of the subjects in the LEVULAN KERASTICK photodynamic therapy group. No subjects in the vehicle group reported itching or scabbing.
Common ( > 2%, <10%) local cutaneous adverse reactions for face, scalp and upper extremities in the LEVULAN KERASTICK topical solution group included wheal, scabbing, pustules, ulceration, bleeding, tenderness and dysesthesia. Uncommon (<2%) local cutaneous adverse reactions for face, scalp and upper extremities in the LEVULAN KERASTICK topical solution group were flaking, pain, peeling, perilesional pruritic rash, excoriation and blistering. Common ( > 2%, <10%) adverse reactions not limited to the application site for upper extremities and occurring more frequently in the LEVULAN KERASTICK topical solution group than in the vehicle group were sinusitis, squamous cell carcinoma, and squamous cell carcinoma of skin.
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of LEVULAN KERASTICK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system disorders : transient amnestic episodes
Warnings & Cautions for Levulan
Transient Amnestic Episodes Transient amnestic episodes have been reported during postmarketing use
of LEVULAN KERASTICK in combination with BLU-U Blue Light Photodynamic Therapy Illuminator. Inform patients and their caregivers that LEVULAN KERASTICK in combination with PDT may cause transient amnestic episodes. Advise them to contact the healthcare provider if the patient develops amnesia after treatment.
Photosensitivity After
LEVULAN KERASTICK topical solution has been applied, the treatment site will become photosensitive and 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) for 40 hours. Exposure may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Therefore, before exposure to sunlight, patients should protect treated lesions from the sun by wearing a wide-brimmed hat or similar head covering of light-opaque material, and/or a long-sleeved shirt and/or gloves.
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 the eye or surrounding skin. Application of LEVULAN KERASTICK topical solution to perilesional areas of photodamaged skin of the face, scalp or upper extremities may result in photosensitization.
Upon exposure to activating light from the BLU-U, such photosensitized skin may produce a stinging and/or burning sensation and may become erythematous and/or edematous in a manner similar to that of actinic keratoses treated with LEVULAN KERASTICK Photodynamic Therapy. Because of the potential for skin to become photosensitized, the LEVULAN KERASTICK topical solution should be used by a qualified health professional to apply drug to no more than 5mm of perilesional skin surrounding the target actinic keratosis lesions. If for any reason the patient cannot return for blue light treatment during the prescribed period after applying LEVULAN KERASTICK topical solution, 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.
Irritation
The LEVULAN KERASTICK topical solution contains alcohol and is intended for topical use only. Irritation may be experienced if this product is applied to eyes or mucous membranes. Do not apply to the eyes or to mucous membranes.
Excessive irritation may be experienced if this product is applied under occlusion longer than 3 hours.
Coagulation Defects
The LEVULAN KERASTICK for topical solution has not been tested on patients with inherited or acquired coagulation defects.
Drug Interactions with Levulan
There have been no formal studies of the interaction of LEVULAN KERASTICK topical solution with any other drugs, and no drug-specific interactions were noted during any of the controlled clinical trials. It is, however, possible that concomitant use of other known photosensitizing agents such as St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides and tetracyclines might increase the photosensitivity reaction of actinic keratoses treated with LEVULAN KERASTICK topical solution . Concomitant use of other known photosensitizing agents such as St.
John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides and tetracyclines might increase the photosensitivity reaction.
Pregnancy Safety for Levulan
Pregnancy Risk Summary Limited available data with LEVULAN KERASTICK topical solution use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Animal developmental toxicology studies were not conducted with aminolevulinic acid. LEVULAN KERASTICK solution has low systemic absorption following topical administration, and the risk of maternal use resulting in fetal exposure to the drug is unknown.
The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Pediatric Use of Levulan
Pediatric Use The safety and effectiveness in pediatric patients below the age of 18 have not been established. Actinic keratosis is not a disease generally seen in the pediatric population.
Contraindications for Levulan
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 Known sensitivity to any of the components of the LEVULAN KERASTICK. Cutaneous photosensitivity at wavelengths of 400-450 nm. Porphyria or known allergies to porphyrins. Sensitivity to any of the components of the LEVULAN KERASTICK.
Overdosage Information for Levulan
LEVULAN
KERASTICK Topical Solution Overdose In the event that the drug is ingested, monitoring and supportive care are recommended. The patient should be advised to avoid incidental exposure to intense light sources for at least 40 hours after ingestion. The consequences of exceeding the recommended topical dosage are unknown.
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.
Clinical Studies of Levulan
Actinic Keratoses of the Face or Scalp
LEVULAN KERASTICK for topical solution plus blue light at 6-
J/cm 2, has been used to treat actinic keratoses of the face
or scalp in 342 subjects in seven clinical trials. Phase 3 trials ALA-018 and ALA-019 were two, identically designed, multicenter, two-arm trials using LEVULAN KERASTICK topical solution plus illumination from the BLU-U Blue Light Photodynamic Therapy Illuminator for 1000 seconds (16 minutes and 40 seconds) for a nominal exposure of 10 J/cm 2. Subjects were excluded from these trials who had a history of cutaneous photosensitization, porphyria, hypersensitivity to porphyrins, photodermatosis, or inherited or acquired coagulation defects. A minimum of 4 and a maximum of 15 clinically typical, discrete, Grade 1 (slightly palpable actinic keratoses: better felt than seen), or Grade 2 (moderately thick actinic keratoses: easily seen and felt) target actinic keratoses were identified (see Table 5 for definitions). Target lesions on the face or on the scalp, but not on both locations in the same subject, received treatment.
The subjects were randomized to receive treatment either with the LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator or vehicle plus BLU-U Blue Light Photodynamic Therapy Illuminator. Subjects were randomized at a 3 to 1 LEVULAN KERASTICK topical solution to vehicle ratio. A total of 243 subjects were enrolled in two Phase 3 trials (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 subjects in whom 75% or more of treated lesions were cleared, and the percentage of subjects in whom 100% of treated lesions were cleared (Complete Responders), for each trial 8 weeks after treatment are shown in Table 4. TABLE 4 - Subject Responses at Week 8 ALA-018 ALA-019 LEVULAN KERASTICK Topical Solution + PDT Vehicle + PDT LEVULAN KERASTICK Topical Solution + PDT Vehicle + PDT Subjects with > 75% of AK Lesions Cleared Total No. Subjects 68/87 (78%) 6/29 (21%) 71/93 (76%) 8/32 (25%) Subjects 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%) Complete Responders Total No. Subjects 60/87 (69%) 4/29 (14%) 59/93 (63%) 4/32 (13%) Subjects with Face Lesions 49/71 (69%) 2/21 (10%) 47/67 (70%) 4/19 (21%) Subjects with Scalp Lesions 11/16 (69%) 2/8 (25%) 12/26 (46%) 0/13 (0%) Because 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 Blue Light Photodynamic Therapy Illuminator is more effective than vehicle plus BLU-U Blue Light Photodynamic Therapy Illuminator, but as shown in Table 5, 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 Blue Light Photodynamic Therapy Illuminator on higher grade lesions was not studied in the Phase 3 clinical efficacy trials. TABLE 5 Lesions Complete Responses at Week 8 for Different Lesion Grades Lesion Grade LEVULAN KERASTICK Topical Solution + PDT Vehicle + PDT Grade 1 (slightly palpable actinic keratoses: better felt than seen) 666/756 (88%) 122/302 (40%) Grade 2 (moderately thick actinic keratoses: easily seen and felt) 495/632 (78%) 52/199 (26%) Grade 3 (very thick and/or hyperkeratotic actinic keratoses) 0 0 Those subjects who were not Complete Responders at Week 8 had retreatment of the persistent target lesions at Week 8. Among the subjects 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 6. TABLE 6 Complete Responders at Week 12, Among Subjects Receiving Two Treatments LEVULAN KERATICK Topical Solution + PDT Vehicle + PDT Total No.
Subjects 24/56 (43%) 2/49 (4%) Subjects with Face Lesions 21/40 (53%) 2/31 (6%) Subjects 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 subjects who received a single treatment as well as the results at 12 weeks for those subjects who received a second treatment at week 8, are shown in Table 7. TABLE 7 Subject Responses at Week 12, Among Subjects Who Received One or Two Treatments LEVULAN KERASTICK Topical Solution + PDT Vehicle + PDT Subjects with > 75% of Actinic Keratosis Lesions Cleared Total No. Subjects 158/180 (88%) 12/61 (20%) Subjects with Face Lesions 127/138 (92%) 8/40 (20%) Subjects with Scalp Lesions 31/42 (74%) 4/21 (19%) Complete Responders Total No. Subjects 129/180 (72%) 7/61 (11%) Subjects with Face Lesions 108/138 (78%) 5/40 (13%) Subjects with Scalp Lesions 21/42 (50%) 2/21 (10%) Among Complete Responders at Week 8, 93% (in ALA-018) and 83% (in ALA-019) maintained complete response at Week 12. Among subjects with scalp lesions, the percentage of subjects with 100% of actinic keratosis lesions having complete response declined from Week 8 (55%) to Week 12 (50%), because there were more subjects with scalp lesions with 100% of actinic keratosis lesions cleared at Week 8 who had a recurrence of a lesion by Week 12 than there were subjects with scalp lesions who had retreatment of persistent lesions at Week 8 and who then achieved 100% of actinic keratosis lesions cleared by Week 12. Subjects did not receive follow-up past 12 weeks after the initial treatment.
Subject outcomes recorded in the two Phase 3 trials are depicted in the following flowchart, in which Complete Responders are designated clear. Seven subjects in the active treatment arm and three subjects in the vehicle treatment arm withdrew or were lost to follow-up. Three subjects in the active treatment arm were treated at baseline but did not return for evaluation until Week 12. One subject in the active treatment arm and two in the vehicle treatment arm who were not clear at Week 8 did not receive retreatment.
An open-label trial enrolled 110 subjects with 4 to 10 clinically typical, discrete actinic keratoses on the face or scalp, but not both locations. The target lesions were treated with the LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator. Any treated lesions that were not clear at Month 2 (Week 8) were re-treated.
Subjects were followed monthly for 12 months. Lesions were designated as cleared 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 percentages of subjects in whom 100% of treated lesions were cleared (Complete Responders) by month, starting at Month 3 (Week 12), are shown in Figure 4. Of the 72 subjects with 100% of treated lesions cleared (Complete Responders) at Month 3, 53% had a recurrence by Month 12. A total of 748 individual lesions were treated; 539 were treated once and 209 were treated twice.
At Month 3, 624 lesions (83%) were cleared. From Month 3 through Month 12 of the trial, 476 lesions (64%) remained clear. See Figure 5. Of the 624 treated lesions determined cleared at Month 3, 24% had recurred by Month 12, while 5% were lost to follow-up and their recurrence status is unknown.
Levulan-05 Levulan-06 Levulan-07
Actinic Keratoses of the Upper Extremities
The safety and efficacy of LEVULAN KERASTICK topical solution plus BLU-U Blue Light Photodynamic Therapy Illuminator at 10J/cm 2 to treat actinic keratoses of the upper extremities has been evaluated in a multicenter randomized, parallel-group, evaluator-blinded, vehicle-controlled trial of 269 subjects. In this trial (CP0108), 269 subjects with 4 -15 mild to moderate actinic keratoses on the upper extremities (dorsal hand/forearm area between the elbow and the base of the fingers) were treated with LEVULAN KERASTICK topical solution and BLU-U Blue Light Photodynamic Therapy Illuminator. Subjects ranged from 45 to 90 years of age (mean 68 years) and 90% had Fitzpatrick Skin Type I, II or III. No subjects had Fitzpatrick Skin Type V or VI. Approximately 70% of subjects were male and all subjects were Caucasian.
Subjects were randomized to treatment in a 1:1 ratio to receive either LEVULAN KERASTICK topical solution or vehicle. Treatment was applied to 4-15 lesions on one dorsal hand/forearm on each subject, and occluded for the three-hour incubation period before treatment with 10 J/cm 2 blue light delivered at 10 mW/cm 2. Treatment was repeated at Week 8 if any actinic keratosis lesions were present in the treatment area. The primary endpoint was the proportion of subjects with complete clearance of all actinic keratosis lesions in the treatment area 12 weeks after initial treatment.
The results of the trial are presented in Table 8. Table 8 – Number and Percentage of Subjects with Actinic Keratosis of the Upper Extremities Achieving Complete Clearance at Week 12 LEVULAN KERASTICK Topical Solution + PDT Vehicle + PDT CP0108 42/135 (31%) 17/134 (13%) Subject outcomes recorded in the trial of the upper extremities are depicted in the following flowchart. Subjects who achieved complete clearance at Week 12 entered a 12-month follow-up period. Subjects who received LEVULAN KERASTICK topical solution with blue light and achieved complete clearance at Week 12 in CP0108A had a recurrence rate of 58% (22/38) at 12 months, where recurrence was defined as the presence of at least one previously treated lesion in the treatment area at any visit during the 12-month follow-up period.
Levulan-08
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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