6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Transient Amnestic Episodes [see Warnings and Precautions (5.1)]. Risk of BF-RhodoLED Lamp Induced Eye Injury [see Warnings and Precautions (5.2)]. Increased Photosensitivity [see Warnings and Precautions (5.3)]. Risk of Bleeding in Patients with Coagulation Disorders [see Warnings and Precautions (5.4)]. Ophthalmic Adverse Reactions [see Warnings and Precautions (5.5)]. Risk of Mucous Membrane Irritation [see Warnings and Precautions (5.6)]. 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 1-844-829-7434 or FDA at 1-800-332-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience 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. 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 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 Adverse reactions at the application site Erythema Pain/Burning Irritation Edema Pruritus Exfoliation Scab Induration Vesicles Paresthesia Hyperalgesia Reaction Discomfort Erosion Discharge Bleeding Pustules 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%) 13 (6%) 8 (4%) 7 (3%) 6 (3%) 4 (2%) 3 (1%) 3 (1%) Common (≥1%, <10%) adverse reactions not at the application site for AMELUZ were headache, skin exfoliation, chills and eyelid edema. Less common (≥0.1%, <1%) adverse reactions at the application site for AMELUZ were hemorrhage and swelling. The adverse reactions not at the application site were blister, feeling hot, pruritus, pyrexia, scab, nervousness, pain, petechiae, rash pustular, skin erosion and ulcer. 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. 6.2 Postmarketing Experience The following adverse reactions have been reported during post-approval use of AMELUZ. 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: application site inflammation, application site discoloration. Eye disorders: eye irritation, diplopia, ocular hyperemia, photophobia, and blurred vision. General disorders and administration site conditions: fatigue. Nervous system disorders: dysaesthesia, transient amnestic episodes.