Red light photodynamic therapy with the BF-RhodoLED®
The cytotoxic reaction of protoporphyrin IX (PpIX) required to destroy AK cells is carried out most effectively when PpIX is illuminated at certain wavelengths. One excitation maximum exists at a wavelength of 635 nm.1
Red light penetrates deeper into tissues than light of shorter wave lengths.1 Ameluz® (aminolevulinic acid hydrochloride) gel, 10% for topical use combines the active substance aminolevulinic acid with a nanoemulsion formulation. Nanoemulsions are known to enhance skin penetration compared to similar formulations without nanoemulsion technology.2 Therefore, the combination of Ameluz® and BF-RhodoLED® was tested for the treatment of actinic keratosis, and has been FDA approved for the lesion-directed and field-directed treatment of actinic keratoses of mild-to-moderate severity on the face and scalp.3
|The principle of photodynamic therapy (left) with red light a potent activator of PpIX, generating an excitation maximum at a wavelength of 635 nm (right).7|
Field-directed PDT is an effective way of preventing AK progression
Due to the unpredictable nature of a potential AK transformation into SCC, two models of progression have been discussed in the scientific literature: Earlier literature suggests a slower, linear transition of AKs that arise from subclinical lesions and become visible at the surface at a later stage, progressing to moderate and severe AKs before transforming into SCC. Recently published data suggests a non-linear, more aggressive pathway that allows immediate transformation into SCC from mild or even subclinical lesions.4
While many keratotic plaques are clinically detectable, a larger area of skin is frequently affected by subclinical lesions in the deeper layers of the epidermis.6 This is why several treatment options offer a field-directed approach to address those premalignant fields of multiple actinic keratoses.
Ameluz® (aminolevulinic acid hydrochloride) gel, 10% is the only PDT drug that has been FDA approved not only for the lesion-directed but also for the field-directed photodynamic therapy. The entire tube of Ameluz® may be applied at a thickness of about 1 mm.
To visualize the underlying damage, doctors may perform fluorescence imaging as part of the photodynamic therapy, after the 3-hour incubation just prior to red-light illumination. By treating entire areas around the individual lesions, all AKs in this area can be treated, irrespective of their visibility.
Preparation and treatment
Ameluz® should only be administered by a healthcare provider. A PDT session is comprised of:
- degreasing the area with alcohol
- removal of crusts, avoiding bleeding
- application of Ameluz®
- 3 hours occlusion
- removal of the residual gel
- subsequent illumination of the entire treatment area with the BF-RhodoLED® at 635 nm and a light dose of approximately 37 J/cm2.
Step 1: Lesion preparation and application of Ameluz®
Initially the skin is degreased with alcohol to cleanse the treatment area. After removing scabs of more moderate actinic lesions, Ameluz® is applied to the affected skin. Special care should be taken to avoid bleeding during lesion preparation in patients with inherited or acquired coagulation disorders. Direct contact of Ameluz® with eyes and the mucous membranes should be avoided.
Ameluz® should be applied at a thickness of 1 mm. No more than 2 grams (one tube) of Ameluz® should be applied at any one time. Larger skin areas may be treated separately or in two office visits.
To avoid a premature reaction, the treatment area is covered with a light occlusive dressing, a process called occlusion.
Step 2: Illumination with the BF-RhodoLED®
After an incubation period of 3 hours the occlusion and any remaining gel is removed, followed by illumination with the BF-RhodoLED® lamp for 10 minutes. Eye exposure to the BF-RhodoLED® light must be prevented. Patients, healthcare providers and any person present during the illumination period must wear protective eyewear before operating the lamp. Avoid staring directly into the light source.
After the treatment, patients should avoid sunlight, prolonged or intense light (e.g., tanning beds, sun lamps) on lesions and surrounding skin treated with Ameluz® for approximately 48 hours following treatment, whether exposed to illumination or not. Lesions must be re-treated if they have not been cleared completely after 3 months.
Most common side effects
Prior to every treatment, patients need to be informed that treatment with Ameluz® in combination with PDT and the BF-RhodoLED® most commonly results in local skin reactions at the application site during illumination or shortly afterwards. These were observed in about 99.5% of patients, were generally of mild or moderate intensity and lasted for 1 to 4 days in most cases. In some cases, however, they persisted for 1 to 2 weeks or even longer. Severe pain/burning occurred in up to 30% of patients.
Most adverse reactions (more or equal to 10%) were application site erythema, pain/burning, irritation, edema, pruritus, exfoliation, scab formation induration, and vesicles. Cooling of the treatment area during and also after PDT usually alleviates the temporary symptoms.
After the treatment
Some patients experience mild to severe pain during PDT, and treated skin frequently shows signs of sterile inflammation. Both adverse reactions indicate that the targeted cells undergo necrotic and apoptotic processes. Patients should be advised not to remove any crusts and to let the healing process take its course. Lesions must be re-treated if they have not been cleared completely after 3 months.
It was demonstrated in clinical trials that about six out of ten patients treated with Ameluz® and the BF-RhodoLED® did not require a second PDT. About 9 out of 10 patients who received one or two treatments with Ameluz® were completely cleared of their AKs.3
1 Peng et al., 1997 Cancer. 1997 Jun 15;79(12):2282-308. 2 Wu et al., J Drug Target, 2013; 21(4): 321-327. 3 Ameluz® Prescribing Information. 4 Fernandez-Figueras et al, J Eur Acad Dermatol Venereol. 2015 May;29(5):991-7. 5 Cockerell CJ, Wharton JR. New histopathological classification of actinic keratosis (incipient intraepidermal squamous cell carcinoma). J Drugs Dermatol 2005; 4: 462–467. 6 Torezan 2013 An Bras Dermatol. 2013;88(5):775-86. 7 Agostinis (2011) CA Cancer J Clin PDT in cancer review. Vol 61. Number 4. 250-281.
For Ameluz® full prescribing information and BF-RhodoLED® user manual information please refer to: www.dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=650daa9f-aeec-49ce-95b9-5fa20b988afd
Important Safety Information
AMELUZ® (aminolevulinic acid hydrochloride) gel, 10% with BF-RhodoLED® lamp
AMELUZ®, containing 10% aminolevulinic acid hydrochloride, is a non-sterile gel formulation for topical use only. Not for ophthalmic, oral, or intravaginal use.
AMELUZ®, in conjunction with lesion preparation, is only to be administered by a health care provider. Photodynamic therapy with AMELUZ® involves preparation of lesions, application of the product, occlusion and illumination with BF-RhodoLED®. The application area should not exceed 20 cm2 and no more than 2 grams of AMELUZ® (one tube) should be used at one time. Lesions that have not completely resolved shall be retreated 3 months after the initial treatment. Refer to BF-RhodoLED® user manual for detailed lamp safety and operating instructions. Both patient and medical personnel conducting the PDT should adhere to all safety instructions.
Ameluz® shall not be used by persons who have known hypersensitivity to porphyrins or any of the components of AMELUZ®, which includes soybean phosphatidylcholine. Ameluz® should also not be used for patients who have porphyria or photodermatoses.
Transient Amnestic Episodes have been reported during postmarketing use of AMELUZ® in combination with photodynamic therapy (PDT). If patients experience amnesia or confusion, discontinue treatment. Advise them to contact the healthcare provider if the patient develops amnesia after treatment.
Eye exposure to the red light of the BF-RhodoLED® lamp during PDT must be prevented by protective eyewear. Direct staring into the light source must be avoided. AMELUZ® increases photosensitivity. Patients should avoid sunlight, prolonged or intense light (e.g., tanning beds, sun lamps) on lesions and surrounding skin treated with AMELUZ® for approximately 48 hours following treatment whether exposed to illumination or not.
AMELUZ® has not been tested on patients with inherited or acquired coagulation disorders. Special care should be taken to avoid bleeding during lesion preparation in such patients. Any bleeding must be stopped before application of the gel. AMELUZ® should not be used on mucous membranes or in the eyes.
Local skin reactions at the application site were observed in about 99.5% of subjects treated with AMELUZ® and narrow spectrum lamps. The very common adverse reactions (≥10%) during and after PDT were application site erythema, pain/burning, irritation, edema, pruritus, exfoliation, scab, induration, and vesicles. Most adverse reactions occurred during illumination or shortly afterwards, were generally of mild or moderate intensity, and lasted for 1 to 4 days in most cases; in some cases, however, they persisted for 1 to 2 weeks or even longer. Severe pain/burning occurred in up to 30% of treatments.
There have been no formal studies of the interaction of AMELUZ® with other drugs. Concomitant use of the following photosensitizing medications may increase the phototoxic reactions after PDT: St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones, and tetracyclines.
There are no available data on AMELUZ® use in pregnant women to inform a drug associated risk. No data are available regarding the presence of aminolevulinic acid in human milk, the effects of aminolevulinic acid on the breastfed infant or on milk production. Safety and effectiveness in pediatric patients below the age of 18 have not been established as AK is not a condition generally seen in the pediatric population. No overall differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Please read the US Full Prescribing Information for Ameluz® and/or US User Manual of BF-RhodoLED® lamp available together at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=650daa9f-aeec-49ce-95b9-5fa20b988afd.
You are encouraged to report side effects of Ameluz®. Please contact Biofrontera Inc. at 1-844-829-7434 or FDA at 1-800-332-1088 or www.fda.gov/medwatch.