FILSUVEZ

FILSUVEZ (birch triterpenes) topical gel is a sterile botanical drug product for topical use and contains birch triterpenes in an oil base. FILSUVEZ is a colorless to slightly yellowish, opalescent, non-aqueous gel. Birch triterpenes is a botanical drug substance composed of a mixture of pentacyclic triterpenes. The botanical drug substance is a dry extract, refined, from birch bark from Betula pendula Roth , Betula pubescens Ehrh., as well as hybrids of both species, quantified to 72-88% (w/w) betulin, 2.4-5.7% (w/w) lupeol, 2.6-4.2% (w/w) betulinic acid, 0.5-1.2% (w/w) erythrodiol, 0.3-0.8% (w/w) oleanolic acid. The structural formulae of the main triterpene constituents are shown in Figure 1. Figure 1: Structure of Triterpene Constituents Betulin Erythrodiol Betulinic acid Oleanolic acid Lupeol Each gram of FILSUVEZ topical gel 10% (w/w) contains 100 mg of birch triterpenes in an oil base of refined sunflower oil. FILSUVEZ contains no additional excipients. Chemical Structure - Betulin Chemical Structure - Erythrodiol Chemical Structure - Betulinic acid Chemical Structure - Oleanolic acid Chemical Structure - Lupeol

FILSUVEZ is indicated for the treatment of wounds associated with dystrophic and junctional epidermolysis bullosa (EB) in adult and pediatric patients 6 months of age and older. FILSUVEZ topical gel is indicated for the treatment of wounds associated with dystrophic and junctional epidermolysis bullosa in adult and pediatric patients 6 months of age and older. ( 1 )

Wash hands before and after applying FILSUVEZ or wear gloves for application. Apply a 1 mm layer of FILSUVEZ to the affected wound surface only. Do not rub in the gel. Cover the wound with a sterile non-adhesive wound dressing. Alternatively, apply FILSUVEZ directly to the dressing so that the topical gel is in direct contact with the wound. Apply FILSUVEZ to cleansed wounds with wound dressing changes until the wound is healed. If a FILSUVEZ-treated wound becomes infected, discontinue treatment to that wound until the infection has resolved. Each tube of FILSUVEZ is for one-time use only. Once the tube is opened, use the product immediately. Discard the tube after use in household trash or through a drug take back site, if available. Avoid contact of FILSUVEZ with eyes and mucous membranes (e.g., mouth, vagina, anus). In case of accidental contact, irrigate the area with water. FILSUVEZ is for topical use only. Not for use on mucous membranes (oral, intravaginal, or intra-anal). Not for ophthalmic use. Apply a 1 mm layer of FILSUVEZ to the affected wound surface and cover with wound dressing or apply FILSUVEZ directly to dressing so that the topical gel is in direct contact with the wound. Do not rub in the topical gel. ( 2 ) Apply FILSUVEZ at wound dressing changes until the wound is healed. ( 2 ) Each tube of FILSUVEZ is for one-time use only. ( 2 ) For topical use; not for oral, intravaginal, intra-anal, or ophthalmic use. ( 2 )

None. None ( 4 )

The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] The most common (incidence ≥2%) adverse reactions are application site reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 safety of FILSUVEZ was evaluated in EASE, a randomized, double-blind, multicenter, placebo-controlled trial in 223 adult and pediatric subjects with inherited EB. During the double-blind phase of EASE, subjects received topical treatment with either FILSUVEZ or a placebo gel on partial-thickness wounds every 1 to 4 days for a total of 90 days. Treated wounds were covered with non-adhesive dressings. Following completion of the double-blind phase, all subjects received FILSUVEZ for a total of 24 months during the open-label phase [see Clinical Studies (14) ] . Table 1 presents adverse reactions that occurred in at least 2% of subjects treated with FILSUVEZ during the 90-day double-blind phase of EASE and at a greater frequency than in the placebo gel group. Table 1: Number (%) of Subjects with Adverse Reactions Occurring in ≥ 2% Adverse Reaction FILSUVEZ (N=109) n (%) Placebo Gel (N=114) n (%) Application site reaction Includes: application site pruritus, administration site pain, administration site pruritus. 8 (7.3) 7 (6.1) Squamous cell carcinoma of the skin (SCC) was reported as an adverse event in the double-blind and open-label periods of EASE. Four subjects with recessive dystrophic EB each reported one SCC: a 20-year-old male on day 1 of the double-blind period; three female subjects ages 22, 46, and 49 years during the open-label period. Two of the four subjects had applied FILSUVEZ to the area which developed the SCC.

Store at 20°C to 25°C (68° F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]). Do not freeze. Do not use beyond the expiration date.