HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
` These highlights do not include all the information needed to use
`
` AMELUZ safely and effectively. See full prescribing information
`
` for AMELUZ.
`
`
`
`AMELUZ® (aminolevulinic acid hydrochloride) gel, 10%, for
`
`
`
`topical use
`
`Initial U.S. approval: 1999
`
`
`
`-------------------------INDICATIONS AND USAGE-------------------­
`AMELUZ gel, a porphyrin precursor, in combination with
`
`
`
`photodynamic therapy using BF-RhodoLED 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).
`
`
`
`
`
`------------------DOSAGE AND ADMINISTRATION----------------­
`
`• 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 (2.2).
`
`
`• Retreat lesions that have not completely resolved 3 months after
`
`
`
`
`
`the initial treatment (2.2).
`
`• See BF-RhodoLED user manual for detailed lamp safety and
`
`operating instructions (2).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`------------------WARNINGS AND PRECAUTIONS------------------­
`• Risk of Eye Injury: Patients and healthcare providers must wear
`
`
`
`
`
`
`protective eyewear before operating BF-RhodoLED lamp (5.1).
`
`
`
`• Photosensitivity: Protect treated lesions from sunlight exposure
`
`
`
`for 48 hours post treatment (5.2).
`
`
`
`
`• Risk of Bleeding: Special care should be taken to avoid bleeding
`
`
`
`
`
`during lesion preparation in patients with inherited or acquired
`
`
`coagulation disorders (5.3).
`
`
`• Ophthalmic Adverse Reactions: Avoid direct contact of
`
`
`
`
`AMELUZ with the eyes (5.4).
`
`• Mucous Membranes Irritation: Avoid direct contact of AMELUZ
`
`
`
`
`
`with the mucous membranes (5.5).
`
`
`
`
`
`
`
`
`--------------------------ADVERSE REACTIONS-----------------------­
`Most common adverse reactions (≥ 10%) were application site
`
`
`
`
`
`
`
`erythema, pain/burning, irritation, edema, pruritus, exfoliation, scab,
`
`
`
`
`induration, and vesicles (6.1).
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`
`Biofrontera Inc. at 1-884-829-7434 or FDA at 1-800-332-1088
`
`
`
`
`or www.fda.gov/medwatch.
`
`
`
`--------------------------DRUG INTERACTIONS------------------------­
`
`
`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).
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`-----------------DOSAGE FORMS AND STRENGTHS---------------­
`Gel: 10% (3).
`
`
`
`
`-------------------------CONTRAINDICATIONS------------------------­
`• Known hypersensitivity to porphyrins (4).
`
`
`• Known hypersensitivity to any component of AMELUZ, which
`
`
`includes soybean phosphatidylcholine (4).
`
`Porphyria (4).
`
`
`•
`Photodermatoses (4).
`
`
`•
`______________________________________________________________________________________________________________________________________
`
`
`
`
`8.4 Pediatric Use
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`8.5 Geriatric Use
`1.
`INDICATIONS AND USAGE
`
`
`
`
`2. DOSAGE AND ADMINISTRATION
`10. OVERDOSAGE
`
`
`
`
`
`Important Administration Information
`2.1
`10.1 AMELUZ Overdose
`
`
`
`
`
`
`2.2 Dosage and Administration Instructions
`10.2 Red Light Overdose following AMELUZ Administration
`
`
`
`
`3. DOSAGE FORMS AND STRENGTHS
`11. DESCRIPTION
`
`
`
`
`4. CONTRAINDICATIONS
`12. CLINICAL PHARMACOLOGY
`
`
`
`
`
`12.1 Mechanism of Action
`5. WARNINGS AND PRECAUTIONS
`
`
`
`
`
`5.1 Risk of BF-RhodoLED Lamp Induced Eye Injury
`12.3 Pharmacokinetics
`
`
`
`
`
`5.2
`Increased Photosensitivity
`13. NONCLINICAL TOXICOLOGY
`
`
`
`
`
`
`5.3 Risk of Bleeding in Patients with Coagulation Disorders
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`5.4 Ophthalmic Adverse Reactions
`
`14. CLINICAL STUDIES
`
`
`
`
`
`5.5 Risk of Mucous Membranes Irritation
`
`16. HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`6. ADVERSE REACTIONS
`17. PATIENT COUNSELING INFORMATION
`
`
`
`
`6.1 Clinical Trial Experience
`17.1 Photosensitivity
`
`
`
`
`
`6.2 Postmarketing Experience
`17.2 Common Adverse Reactions
`
`
`7. DRUG INTERACTIONS
`
`
`8. USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Lactation
`
`
`Revised: 05/2016
`
`
`
`*Sections or subsections omitted from the full prescribing
`information are not listed
`
`______________________________________________________________________________________________________________________________________
`
`
`
`
`Reference ID: 3929378
`
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`Page 1 of 11
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`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1.
`
`
`AMELUZ® gel, in combination with photodynamic therapy (PDT) using BF-RhodoLED® 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.
`
`
`2. DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`Important Administration Information
`
`
`
`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 light. Retreat lesions that have not completely resolved after 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.
`
`
`Dosage and Administration Instructions
`2.2
`
`
`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.
`
`
`Reference ID: 3929378
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` 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 cm2 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
`
`
`
` BF-RhodoLED®, a red light source with a narrow spectrum around 635 nm that delivers a light
`
`
`
` dose of approximately 37 J/cm2 within 10 minutes. Calibration by the operator is not needed; the
`
`
`
`
`
`
`illumination time is calculated automatically. Position the lamp head 5-8 cm from the skin’s
`
`
`
`
`surface. When an area of 8 x 18 cm is illuminated, the effective treatment area is 6 x16 cm.
`
`
`
`
`
`Larger areas can be illuminated in several steps.
`
`
`
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`
`
`Reference ID: 3929378
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` Page 3 of 11
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` Healthy untreated skin surrounding the AK lesions does not need protection during illumination.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Figure 4: Illumination
` 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).
`
`
`
`
`
`
` 3. DOSAGE FORMS AND STRENGTHS
`
` Each gram of AMELUZ gel, 10% contains 100 mg of aminolevulinic acid hydrochloride
`
`
`
`
` (equivalent to 78 mg of aminolevulinic acid).
`
`
`
`4. CONTRAINDICATIONS
`
`
`AMELUZ is contraindicated in patients with:
`
`
`
`• Known hypersensitivity to porphyrins.
`
`
`
`• Known hypersensitivity to any of the components of AMELUZ, which includes soybean
`
`
`
`
`
`
`phosphatidylcholine.
`
`• Porphyria. AMELUZ use may cause uncontrolled phototoxic effects [see Warnings and
`
`
`
`
`Precautions (5.2)].
`
`• Photodermatoses. PDT may worsen the phototoxic or photoallergic reactions [see
`
`
`
`Warnings and Precautions (5.2)].
`
`
`
`
`
`
`5. WARNINGS AND PRECAUTIONS
`
`
`5.1
`Risk of BF-RhodoLED Lamp Induced Eye Injury
`
`
`
`
`
`BF-RhodoLED 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 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)].
`
`
`
`Increased Photosensitivity
`5.2
`
`
`
`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
`
`
`
`
`
`Reference ID: 3929378
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` Page 4 of 11
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`
`
`
`
`
`
` with other known photosensitizing agents may increase the risk of phototoxic reaction to PDT
`
`
`
` [see Drug Interactions (7)].
` Risk of Bleeding in Patients with Coagulation Disorders
`
`
`
`5.3
`
` 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.
`
`
`
`
`
` Ophthalmic Adverse Reactions
` 5.4
` 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.
`
`
`
`Risk of Mucous Membrane Irritation
`5.5
`
`
`
`
`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.
`
`
`
`
`
`6. ADVERSE REACTIONS
`
`
`
`The following adverse reactions are discussed in greater detail in other sections of the labeling:
`
`
`
`• Risk of BF-RhodoLED Lamp Induced Eye Injury[see Warnings and Precautions (5.1)].
`
`
`
`
`
`Increased Photosensitivity [see Warnings and Precautions (5.2)].
`
`
`
`
`
`•
`• Risk of Bleeding in Patients with Coagulation Disorders [see Warnings and Precautions
`
`
`
`
`(5.3)].
`
`• Ophthalmic Adverse Reactions [see Warnings and Precautions (5.4)].
`
`
`
`
`
`• Risk of Mucous Membranes Irritation [see Warnings and Precautions (5.5)].
`
`
`
`
`
`
`
`
`
`Clinical Trial Experience
`6.1
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
`
`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.
`
`
`
`
`The clinical program for AMELUZ included three double-blind and placebo-controlled trials
`
`
`
`
`(Trials 1, 2, and 3), enrolling a total of 299 subjects that were treated with narrow band light.
`
`
`
`Trial subjects were adults greater than or equal to 49 years of age, and the majority 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.
`
`
`For all trials, the enrolled subjects had mild to moderate AKs (Olsen grade 1 and 2) with 4 to 8
`
`
`
`
`
` lesions on the face and scalp. Overall, 87 placebo-treated subjects (n=16, n=32, n=39) and 212
`
`
`
`
`
`
` AMELUZ-treated subjects (n=32, n=55, and n=125) were illuminated with BF-RhodoLED or
`
`
`
`
`
`
`
` similar narrow spectrum lamps.
`
`
`
` Local skin reactions at the application site were observed in about 99.5% of subjects treated with
`
`
`
`
`
`
`
` AMELUZ and narrow spectrum lamps. The most frequent adverse reactions during and after
` PDT were application site erythema, pain, burning, irritation, edema, pruritus, exfoliation, scab,
`
`
`
`
`
`
`
`
` induration, and vesicles.
`
`
`
`
`Reference ID: 3929378
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` Page 5 of 11
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`

`

` 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 subjects.
`
`
`
` In one case, the adverse reactions required interruption or discontinuation of the illumination.
`
`
`
`
` The incidence of common (≥1%, <10%) and very common (≥10%) adverse reactions in
`
`
`
` randomized, multicenter trials trials at the application site are presented in Table 1.
`
`
`
`
`
`
`
`
`
`
`
`Table 1: Incidence of Adverse Reactions Occurring at ≥ 1% of the AMELUZ Group and
`
`
`
`
`More Frequently than the Vehicle Group in the Actinic Keratosis Trials at the Application
`
`Site
` Adverse reaction
`
`
`
`
`
` Vehicle
`
`
` n=87
`
`
`
`AMELUZ
`
` n=212
`
`
`
`
`
` 34 (39%)
`
` 26 (30%)
`
` 17 (20%)
`
` 3 (3%)
` 14 (16%)
`
`
`
` 4 (5%)
` 2 (2%)
`
`
` 0 (0%)
`
` 1 (1%)
`
` 2 (2%)
`
` 0 (0%)
`
` 2 (2%)
`
` 0 (0%)
`
` 0 (0%)
`
` 0 (0%)
`
`
` 0 (0%)
`
` 0 (0%)
`
`
` 195 (92%)
`
` 195 (92%)
`
` 153 (72%)
`
` 75 (35%)
`
` 72 (34%)
`
` 41 (19%)
`
`
` 41 (19%)
`
` 26 (12%)
`
`
` 25 (12%)
`
`
` 18 (9%)
`
`
` 10 (5%)
`
` 8 (4%)
`
`
` 7 (3%)
`
` 6 (3%)
`
` 4 (2%)
`
`
` 3 (1%)
`
` 3 (1%)
`
`
`
`
`
`Adverse reactions at the
`
` application site
`
` Erythema
` Pain/Burning
`
` Irritation
`
` Edema
` Pruritus
`
` Exfoliation
`
` Scab
` Induration
`
` Vesicles
` Paresthesia
`
` Hyperalgesia
`
` Reaction
` Discomfort
`
` Erosion
` Discharge
`
` Bleeding
`
` Pustules
`
`
`
`
`
`
`
`
`
`
`
`
`Common (≥1%, < 10%) adverse reactions not limited to the application site were chills,
`
`
`
`
`
`
`
`headache, and skin exfoliation.
`
`
`
`Uncommon (≥ 0.1%, <1%) adverse reactions at the application site for AMELUZ were
`
`
`
`
`
`
`hemorrhage and swelling. The adverse reactions not limited to the application site were eyelid
`
`
`
`
`
`
`
`edema, feeling hot, pain, pyrexia, ulcer, hyperalgesia, rash pustular, nervousness, blister,
`
`
`
`petechiae, pruritus, scab and skin erosion.
`
`
`In a clinical trial designed to investigate the sensitization potential of aminolevulinic acid with
`
`
`
`
`216 healthy subjects, 13 subjects (6%) developed allergic contact dermatitis after continuous
`
`exposure for 21 days with doses of aminolevulinic acid that were higher than doses normally
`
`
`
`used in the treatment of AK.
`
`
`
`
`Reference ID: 3929378
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` Page 6 of 11
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`Postmarketing Experience
`6.2
`
`
`
`
`
`In addition to adverse reactions reported from clinical trials, the following adverse reactions have
`
`
`
`
`
`
`
`been reported during post-approval use of AMELUZ outside the United States. 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.
`
`
`
`Skin and subcutaneous tissue disorders: erythema, swelling, application site inflammation and
`
`
`
`
`skin discoloration.
`
`
`
`Eye disorders: eye irritation, diplopia, ocular hyperemia, photophobia, and blurred vision.
`
`
`
`
`
`
` 7. DRUG INTERACTIONS
`
`
` 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 (5.1)].
`
`
`
`
`
`
`
`8. USE IN SPECIFIC POPULATIONS
`
`
`
`
`8.1
`Pregnancy
`
`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.
`
`Lactation
`8.2
`
`
`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.
`
`
`
`Reference ID: 3929378
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` Page 7 of 11
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`Pediatric Use
`8.4
`
`
`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.
`
`8.5
`Geriatric Use
`
`
`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.
`
`
`
`10. OVERDOSAGE
`
`
`10.1
`AMELUZ Overdose
`
`
`
`AMELUZ overdosage following topical administration has not been reported. If AMELUZ is
`
`
`
`
`accidentally ingested, monitoring and supportive care is recommended. The patient should be
`
`
`
`
`advised to avoid incidental sunlight exposure for 48 hours after ingestion.
`
`
`
`Red Light Overdose following AMELUZ Administration
`10.2
`
`
`
`There is no information on overdose of red light from the BF-RhodoLED following AMELUZ
`
`
`
`
`
`application.
`
`
`11. DESCRIPTION
`
`
`AMELUZ (aminolevulinic acid hydrochloride) gel, 10% for topical use 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
`
`
`
`
`
`.HCl . The structural formula of aminolevulinic acid hydrochloride is represented
`C5H9NO3
`
`
`
`
`
`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, propylene glycol, sodium
`
`
`benzoate and purified water.
`
`
`
`Reference ID: 3929378
`
`
`
`
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`
`
` Page 8 of 11
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`
`

`

`
`
`12. CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`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 illumination, which provides a red light of
`
`
`
`
`
`
`narrow spectrum and a light dose of approximately 37 J/cm2 .
`
`
`
`
`
`
`
`Pharmacokinetics
`12.3
`
`
`
`
`
`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 cm2. 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 (Cmax ) 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 Tmax
`
`
`
`(time at which Cmax 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 Cmax 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.
`
`
`
`13. NONCLINICAL TOXICOLOGY
`
`
`
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`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.
`
`
`Reference ID: 3929378
`
`
`
`
`
`
`
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` Page 9 of 11
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`

`

`
`
`14. CLINICAL STUDIES
`
`
`
`
`
`
`
`
`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/cm2. 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/cm2 .
`
`
`
`
`
`
` 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
`
` Narrow Spectrum PDT
`
`
`
`
` AMELUZ
` Vehicle
`
` 5/39 (13%)
` 106/125 (85%)
`
` Trial 1
`
` 2/16 (13%)
`
` 27/32 (84%)
`
` Trial 2
`
` 7/32 (22%)
`
` 50/55 (91%)
`
` Trial 3
` 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.
`
`
`
`
` In a clinical trial designed to investigate the sensitization potential of aminolevulinic acid
` hydrochloride with 216 healthy subjects, 13 subjects (6%) developed allergic contact dermatitis
`
`
`
`
`
`
` after continuous exposure for 21 days with doses of aminolevulinic acid hydrochloride that were
` higher than doses normally used in the treatment of AK.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3929378
`
`
`
`
`
`
`
`
` Page 10 of 11
`
`
`

`

`
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`
`
`16. HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`
`
`
`AMELUZ (aminolevulinic acid hydrochloride) 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.
`
`
`
`
`2 g tube
`NDC 70621-101-01
`
`
`
`
`
`
`
`
`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.
`
`
`
`17. PATIENT COUNSELING INFORMATION
`
`
`17.1
`Photosensitivity
`
`
`
`
`Advise patients that for approximately 48 hours following treatment to avoid exposure to
`
`
`
`sunlight, and prolonged or intense light on the treated lesion sites and surrounding skin.
`
`
`Advise patients to avoid certain medications that may enhance the phototoxic reaction to PDT
`[see Warnings and Precautions (5) and Drug Interactions (7)].
`
`
`17.2
`Common Adverse Reactions
`
`
`
`
`
`
`
`Inform patients that treatment with AMELUZ in combination with PDT may result in adverse
`
`
`reactions which include local skin reactions at the application site such as erythema,
`
`
`
`
`pain/burning, irritation, edema, pruritus, exfoliation, induration, scab, and vesicles.
`
`
`
`
`
`
`
`AMELUZ and BF-RhodoLED are registered trade marks of Biofrontera Pharma GmbH.
`
`PATENT INFO
`
`US patent 6,559,183 and pending patent application US 2009/0324727
`
`
`
`Distributed by:
`
` Biofrontera Inc.
`
` 201 Edgewater Dr.
`
` Wakefield, MA 01880
`
` USA
`
`
`
`
`
`
`Reference ID: 3929378
`
`
`
`
`
`
`
`
` Page 11 of 11
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`

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`New Drug Application (NDA): 208081
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`Products on NDA 208081
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`EMA
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`
`CSV Excel|Print
`
`Drug Name STLa| Ptr eM Ue)PMU Crt ated
`
`
`AMINOLEVULINIC ACID HYDROCHLORIDE 10% ‘GEL;TOPICAL Prescription None YesAMELUZ Yes
`
`
`
`
`
`
`
`Marketing Status 00
`
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`Approval Date(s) and History, Letters, Labels, Reviews for NDA 208081
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`05/25/2021
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`SUPPL-11
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`Labeling-Package Insert
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`Label (PDF)
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`09/06/2017
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