DailyMed Label: AMELUZ

DailyMed Label: AMELUZ

2024

DailyMed Prescription

AMELUZ

aminolevulinic acid hydrochloride

Biofrontera Inc.

NDC: 70621-101

NDC: 70621-101

NDC: 70621-101

NDC: 70621-101

NDC: 70621-101

AMELUZ (aminolevulinic acid hydrochloride) topical gel, 10% is a non-sterile white-to-yellowish gel. The gel formulation contains a nanoemulsion. Aminolevulinic acid, a porphyrin precursor, is a white to off-white crystalline solid. It is readily soluble in water, methanol, and dimethylformamide. Its chemical name is 5-amino-4-oxo-pentanoic acid hydrochloride, molecular weight is 167.59 and molecular formula is C 5 H 9 NO 3 ·HCl. The structural formula of aminolevulinic acid hydrochloride is represented below: Each gram of AMELUZ contains 100 mg of aminolevulinic acid hydrochloride (equivalent to 78 mg aminolevulinic acid) as the active ingredient and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglycerides, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, sodium benzoate and purified water. ALA.HCl - Structural Formula

AMELUZ, in combination with photodynamic therapy (PDT) using BF-RhodoLED ® or RhodoLED ® XL lamp, a narrowband, red light illumination source, is indicated for lesion-directed and field-directed treatment of actinic keratoses (AKs) of mild-to-moderate severity on the face and scalp. AMELUZ, a porphyrin precursor, in combination with photodynamic therapy using BF-RhodoLED or RhodoLED XL lamp, is indicated for the lesion-directed and field-directed treatment of actinic keratoses of mild-to-moderate severity on the face and scalp ( 1 ).

Administer AMELUZ only by a health care provider ( 2.1 ). AMELUZ is for topical use only ( 2.1 ). Photodynamic therapy with AMELUZ involves preparation of lesions, application of the product, occlusion and illumination with BF-RhodoLED or RhodoLED XL lamp ( 2.2 ). Retreat lesions that have not completely resolved 3 months after the initial treatment ( 2.1 ). See BF-RhodoLED or RhodoLED XL user manual for detailed lamp safety and operating instructions ( 2.1 ). AMELUZ, in conjunction with lesion preparation, is only to be administered by a health care provider. AMELUZ is for topical use only. Not for ophthalmic, oral, or intravaginal use. Treat single lesions or an entire field affected by multiple lesions with AMELUZ, in combination with red light photodynamic therapy (PDT). PDT requires administration of both AMELUZ and BF-RhodoLED or RhodoLED XL light. Retreat lesions that have not completely resolved after 3 months after the initial treatment. Refer to BF-RhodoLED or RhodoLED XL user manual for detailed lamp safety and operating instructions. Both patient and medical personnel conducting the PDT should adhere to all safety instructions. PDT is a multi-stage process: Step 1. Preparation of Lesions Before applying AMELUZ, carefully wipe all lesions with an ethanol or isopropanol-soaked cotton pad to ensure degreasing of the skin. Figure 1A: Degreasing the skin Thereafter, remove any scaling and crusts and gently roughen all lesion surfaces, taking care to avoid bleeding. Figure 1B: Removal of scales and crust Step 2. Application of AMELUZ Use glove protected fingertips or a spatula to apply AMELUZ. Apply gel approximately 1 mm thick and include approximately 5 mm of the surrounding skin. Use sufficient amount of gel to cover the single lesions or if multiple lesions, the entire area. Application area should not exceed 20 cm 2 and no more than 2 grams of AMELUZ (one tube) should be used at one time. The gel can be applied to healthy skin around the lesions. Avoid application near mucous membranes such as the eyes, nostrils, mouth, and ears (keep a distance of 1 cm from these areas). In case of accidental contact with these areas, thoroughly rinse with water. Allow the gel to dry for approximately 10 minutes before applying occlusive dressing. Figure 2: Drug application Step 3. Occlusion for 3 Hours Cover the area where the gel has been applied with a light-blocking, occlusive dressing. Following 3 hours of occlusion, remove the dressing and wipe off any remaining gel. Figure 3: Occlusion Step 4. Illumination with Red Light During illumination, patient and medical personnel need to wear suitable protective eyewear. Immediately after removing occlusion and any remaining gel, illuminate the treatment area with the BF-RhodoLED or RhodoLED XL lamp. BF-RhodoLED and RhodoLED XL lamps are red light sources with a narrow spectrum around 635 nm that deliver a light dose of approximately 37 J/cm 2 . Calibration by the operator is not needed; the illumination time is calculated automatically.  Either the BF-RhodoLED or RhodoLED XL lamp can be used: BF-RhodoLED has an effective treatment area of 6 x 16 cm when an area of 8 x 18 cm is illuminated. Position the lamp head 5-8 cm from the skin’s surface. Larger areas can be illuminated in several steps. RhodoLED XL has a curved configuration with an effective treatment area up to 23 x 29 cm. Position the lamp head of the RhodoLED XL 11-14 cm from the skin’s surface. This usually allows a full-face illumination with the use of 5 panels. The smallest recommended number of panels to be used are 3 adjacent panels (see chapter 8.4.6 of RhodoLED XL user manual). Healthy untreated skin surrounding the AK lesions does not need protection during illumination. Figure 4A: Illumination with BF-RhodoLED Figure 4B: Illumination with RhodoLED XL If for any reason, the lesions cannot be illuminated within 3 hours after AMELUZ application, rinse off the gel with saline and water. For 2 days, protect the lesion sites and surrounding skin from sunlight or prolonged or intense light (e.g., tanning beds, sun lamps). Figure 1A: Degreasing of the skin Figure 1B: Figure 1B: Removal of scales and crusts Figure 2: Drug application Figure 3: Occlusion Figure 4A: Illumination Figure 4B: Illumination

Each gram of AMELUZ topical gel, 10% contains 100 mg of aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid). Gel: 10% ( 3 ).

AMELUZ is contraindicated in patients with: Known hypersensitivity to porphyrins. Known hypersensitivity to any of the components of AMELUZ, which includes soybean phosphatidylcholine [see Warnings and Precautions (5.1) ] . Porphyria. AMELUZ use may cause uncontrolled phototoxic effects [see Warnings and Precautions (5.4) ] . Photodermatoses. PDT may worsen the phototoxic or photoallergic reactions [see Warnings and Precautions (5.4) ] . Known hypersensitivity to porphyrins ( 4 ). Known hypersensitivity to any component of AMELUZ, which includes soybean phosphatidylcholine ( 4 ). Porphyria ( 4 ). Photodermatoses ( 4 ).

Hypersensitivity reactions have been reported with the use of AMELUZ prior to photodynamic therapy (PDT). AMELUZ should be washed off and appropriate therapy instituted ( 5.1 ). Transient Amnestic Episodes have been reported with use of AMELUZ in combination with PDT. If patients experience amnesia or confusion, discontinue treatment and contact healthcare provider ( 5.2 ). Risk of Eye Injury: Patients and healthcare providers must wear protective eyewear before operating BF-RhodoLED or RhodoLED XL lamp ( 5.3 ). Photosensitivity: Protect treated lesions from sunlight exposure for 48 hours post treatment ( 5.4 ). Risk of Bleeding: Special care should be taken to avoid bleeding during lesion preparation in patients with inherited or acquired coagulation disorders ( 5.5 ). Ophthalmic Adverse Reactions: Avoid direct contact of AMELUZ with the eyes ( 5.6 ). Mucous Membrane Irritation: Avoid direct contact of AMELUZ with the mucous membranes ( 5.7 ). Several cases of hypersensitivity were reported during postmarketing use of AMELUZ prior to PDT illumination [ see Adverse Reactions (6.2) ]. If allergic reactions occur, clean the area of skin where the product was applied and institute appropriate therapy. Inform patients and their caregivers that AMELUZ may cause hypersensitivity, potentially including severe courses (anaphylaxis). Transient amnestic episodes have been reported during postmarketing use of AMELUZ in combination with photodynamic therapy. Inform patients and their caregivers that AMELUZ in combination with photodynamic therapy may cause transient amnestic episodes. Advise them to contact the healthcare provider if the patient develops amnesia after treatment. BF-RhodoLED or RhodoLED XL lamp may cause eye irritation, glare, or injury. Before operating the lamp, personnel must refer to the user manual for specific warnings, cautions, and instructions. Eye exposure to the BF-RhodoLED or RhodoLED XL light must be prevented. Protective eye equipment must be used by patient, healthcare providers and any person present during the illumination period. Avoid staring directly into the light source [see Dosage and Administration (2) ] . AMELUZ increases photosensitivity. 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. Concomitant use of AMELUZ with other known photosensitizing agents may increase the risk of phototoxic reaction to PDT [see Drug Interactions (7) ] . 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 [see Dosage and Administration (2) ] . Any bleeding must be stopped before application of the gel. Eyelid edema has occurred with AMELUZ application. AMELUZ can cause ophthalmic adverse reactions. AMELUZ is intended for topical use only. Do not apply AMELUZ into the eyes. Rinse eyes with water in case of accidental contact. AMELUZ can cause mucous membrane irritation. AMELUZ is intended for topical use only. Do not apply AMELUZ to the mucous membranes. Rinse with water in case of accidental contact.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

There have been no formal studies of the interaction of AMELUZ with other drugs. It is possible that concomitant use of other known photosensitizing agents such as St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones and tetracyclines may enhance the phototoxic reaction to PDT [see Warnings and Precautions (5.3) ] . Concomitant use of the following medications may enhance the phototoxic reaction to photodynamic therapy: St. John’s wort, griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulphonamides, quinolones, and tetracyclines ( 7 ).

Risk Summary There are no available data on AMELUZ use in pregnant women to inform a drug associated risk. Animal reproduction studies were not conducted with aminolevulinic acid. Systemic absorption of aminolevulinic acid in humans is negligible following topical administration of AMELUZ under maximal clinical use conditions [see Clinical Pharmacology (12.3) ] . It is not expected that maternal use of AMELUZ will result in fetal exposure to the drug. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. 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. Risk Summary 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. However, breastfeeding is not expected to result in exposure of the child to the drug due to the negligible systemic absorption of aminolevulinic acid in humans following topical administration of AMELUZ under maximal clinical use conditions [see Clinical Pharmacology (12.3) ] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AMELUZ and any potential adverse effects on the breastfeeding child from AMELUZ or from the underlying maternal condition. Safety and effectiveness in pediatric patients below the age of 18 have not been established. AK is not a condition generally seen in the pediatric population. Of the 384 subjects exposed to AMELUZ in randomized, multicenter clinical trials, 83% (318/384) of the subjects were 65 years old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

AMELUZ (aminolevulinic acid hydrochloride) topical gel, 10% is a white-to-yellowish gel. The drug product is supplied in an aluminum tube with a white, high density polyethylene (HDPE) screw cap. Each tube contains 2 g of gel. NDC 70621-101-01 2 g tube NDC 70621-101-10 Cardbox containing one 2 g tube NDC 70621-101-20 Cardbox containing ten 2 g tubes Store AMELUZ in a refrigerator, 2°C – 8°C (36°F – 46°F). Excursions permitted to 15°C – 30°C (59°F – 86°F). After opening, AMELUZ can be stored for up to 12 weeks in a refrigerator at 2°C – 8°C (36°F – 46°F) if the tube is tightly closed.

Photoactivation following topical application of AMELUZ occurs when aminolevulinic acid (prodrug) is metabolized to protoporphyrin IX (PpIX), a photoactive compound which accumulates in the skin. When exposed to red light of a suitable wavelength and energy, PpIX is activated resulting in an excited state of porphyrin molecules. In the presence of oxygen, reactive oxygen species are formed which causes damage to cellular components, and eventually destroys the cells. AMELUZ photodynamic therapy of AK lesions utilizes photoactivation of topically applied AMELUZ resulting from BF-RhodoLED or RhodoLED XL illumination, which provides a red light of narrow spectrum and a light dose of approximately 37 J/cm 2 . The pharmacodynamics of AMELUZ in the treatment of actinic keratosis are unknown. Pharmacokinetics (PK) of aminolevulinic acid and PpIX was evaluated in a trial of 12 adult subjects with mild to moderate AK with at least 10 AK lesions on the face or forehead. A single dose of one entire tube of AMELUZ (2 grams) was applied under occlusion for 3 hours followed by PDT to a total area of 20 cm 2 . The mean ± SD baseline plasma aminolevulinic acid and PpIX concentrations were 20.16 ± 16.53 ng/mL and 3.27 ± 2.40 ng/mL, respectively. In most subjects, an up to 2.5-fold increase of aminolevulinic acid plasma concentrations was observed during the first 3 hours after AMELUZ application. The mean ± SD area under the concentration time curve (AUC 0-t ) and maximum concentration (C max ) for baseline corrected aminolevulinic acid (n=12) were 142.83 ± 75.50 ng.h/mL and 27.19 ± 20.02 ng/mL, respectively. The median T max (time at which C max occurred) was 3 hours. The majority (about 55%) of the PpIX concentrations were below the limit of quantification (LOQ = 1 ng/mL) and baseline corrected values were negative in all subjects except for one. The baseline corrected AUC 0-t and C max in the single subject was 0.07 ng.h/mL and 0.29 ng/mL, respectively. PK of aminolevulinic acid and PpIX following treatment on the scalp was not evaluated.

Long-term studies to evaluate the carcinogenic potential of AMELUZ or aminolevulinic acid have not been performed. Aminolevulinic acid revealed no evidence of mutagenic or clastogenic potential based on the results of three in vitro genotoxicity tests (Ames assay, HPRT test in V79 cells, and Human lymphocyte chromosomal aberration assay) and one in vivo genotoxicity test (mouse micronucleus assay). These genotoxicity studies were conducted without exposure to light. There is a literature report that indicates that aminolevulinic acid may cause genotoxic effects in the presence and in the absence of activating light. These genotoxic effects are likely caused by the formation of reactive oxygen species. Animal fertility studies have not been conducted with aminolevulinic acid because of the negligible systemic absorption of aminolevulinic acid in humans following topical administration of AMELUZ under maximal clinical use conditions.

The efficacy and safety of AMELUZ in combination with PDT using a narrow spectrum (red light lamp) source were evaluated in three randomized, multicenter trials (Trials 1, 2, and 3). Trials 2 and 3 were vehicle-controlled and double-blind. Trial 1 was double-blind with respect to vehicle and observer-blind regarding the active comparator arm. All clinical trials included a follow-up assessment after 6 and 12 months. In these trials, 212 subjects with 4 to 8 mild to moderate AK lesions on the face/forehead and/or bald scalp were treated with AMELUZ and a narrow band spectrum lamp. Subjects ranged from 49 to 87 years of age (mean 71 years), and 92% had Fitzpatrick skin type I, II, or III. No subjects had Fitzpatrick skin type V or VI. Approximately 86% of subjects were male, and all subjects were Caucasian. All sessions were comprised of lesion preparation to roughen the surface and remove crusts, application of AMELUZ with occlusion for 3 hours, and removal of the residual gel. Subsequently, the entire treatment area was illuminated with a narrow spectrum red light source, a lamp of either 630 nm or 633 nm and a light dose of approximately 37 J/cm 2 . In Trial 3, illumination was performed with BF-RhodoLED, a red light source with a narrow spectrum around 635 nm and a light dose of approximately 37 J/cm 2 . In all trials, the lesions that were not completely cleared 12 weeks after the initial treatment were treated a second time with an identical regimen. In the trials, 42% (88/212) of subjects needed a second treatment. The primary endpoint for all trials was complete clearance 12 weeks after the last PDT. The results of Trials 1, 2 and 3 are presented in Table 2. Table 2: Complete Clearance 12 Weeks After the Last Narrow Spectrum PDT in Subjects with Actinic Keratoses AMELUZ Vehicle Trial 1 106/125 (85%) 5/39 (13%) Trial 2 27/32 (84%) 2/16 (13%) Trial 3 50/55 (91%) 7/32 (22%) Subjects who achieved complete clearance at 12 weeks after the last PDT entered a 12-month follow-up period. In the three trials, subjects who received AMELUZ with the narrowband PDT and achieved complete clearance 12 weeks after the last PDT had recurrence rates of 14%, 11%, and 25%, respectively (at 6 months) and 40%, 22%, and 37%, respectively (at 12 months). Recurrence was defined as the percentage of subjects with at least one recurrent lesion during the 6-month or 12-month follow-up period in subjects with completely cleared lesions 12 weeks after the last PDT.

Outer Packaging, single Carton NDC 70621-101-10 Ameluz ® Rx Only (aminolevulinic acid HCl) topical gel, 10% Use contents within 3 months after opening. Discard after: __/ __/ __. Store refrigerated 2°-8°C (36°-46°F), excursions permitted to 15°-30°C (59°-86°F). Keep out of the sight and reach of children. See package insert for dosage information. Net Wt. 2 g Distributed By: Biofrontera Inc. 120 Presidential Way, Suite 330 Woburn, MA 01801 Product of Switzerland For Topical Use Only with BF-RhodoLED ® or RhodoLED ® XL lamp Healthcare Professionals Only Ingredients: Each gram of Ameluz Gel contains 100 mg of the active ingredient, aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid) and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglyceride, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, sodium benzoate and purified water Outer Packaging, Physician's Sample NDC 70621-101-30 Ameluz ® Rx Only Physician's Sample Not for sale (aminolevulinic acid HCl) topical gel, 10% Use contents within 3 months after opening. Discard after: __/ __/ __. Store refrigerated 2°-8°C (36°-46°F), excursions permitted to 15°-30°C (59°-86°F). Keep out of the sight and reach of children. See package insert for dosage information. Net Wt. 2 g Distributed By: Biofrontera Inc. 120 Presidential Way, Suite 330 Woburn, MA 01801 Product of Switzerland For Topical Use Only with BF-RhodoLED ® lamp or RhodoLED ® XL lamp Healthcare Professionals Only Ingredients: Each gram of Ameluz Gel contains 100 mg of the active ingredient, aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid) and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglyceride, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, sodium benzoate and purified water Outer Packaging, Multipack 10 tubes with Net Wt. 2g each NDC 70621-101-20 Ameluz ® Rx Only (aminolevulinic acid HCl) topical gel, 10% For Topical Use Only with BF-RhodoLED ® lamp or RhodoLED ® XL lamp Healthcare Professionals Only See package insert for dosage information. Distributed By: Biofrontera Inc. 120 Presidential Way, Suite 330 Woburn, MA 01801 Product of Switzerland 10 tubes with Net Wt. 2g each NDC 70621-101-20 Ameluz ® Rx Only (aminolevulinic acid HCl) topical gel, 10% Use contents within 3 months after opening the individual tube. Place the enclosed Discard after: __/ __/ __.tag on tube once opened. Store refrigerated 2°-8°C (36°-46°F), excursions permitted to 15°-30°C (59°-86°F). Keep out of the sight and reach of children. See package insert for dosage information. Ingredients: Each gram of Ameluz Gel contains 100 mg of the active ingredient, aminolevulinic acid hydrochloride (equivalent to 78 mg of aminolevulinic acid) and the following inactive ingredients: xanthan gum, soybean phosphatidylcholine, polysorbate 80, medium-chain triglyceride, isopropyl alcohol, dibasic sodium phosphate, monobasic sodium phosphate, sodium benzoate and purified water Distributed By: Biofrontera Inc. 120 Presidential Way, Suite 330 Woburn, MA 01801 Product of Switzerland figure6