Birch Triterpenes

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 )

Topical gel: 10% birch triterpenes w/w in a colorless to slightly yellowish, opalescent, non-aqueous gel supplied in 25 mL sterile tubes. Topical gel: 10% birch triterpenes w/w supplied in 25 mL sterile tubes ( 3 )

None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : If signs or symptoms of hypersensitivity occur, discontinue use immediately and initiate appropriate therapy. ( 5.1 )

5.1 Hypersensitivity Reactions Local hypersensitivity and skin reactions have been reported in patients treated with FILSUVEZ, including urticaria and dermatitis. If signs and symptoms of local or systemic hypersensitivity occur, discontinue FILSUVEZ immediately and initiate appropriate therapy.

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 Amryt Pharmaceuticals DAC at 1-855-303-2347 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.

8.1 Pregnancy Risk Summary There are no available data with use of FILSUVEZ in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In an animal reproduction study, oral administration of birch triterpenes to pregnant rats during the period of organogenesis had no effects on reproductive or fetal parameters (see Data ) . Systemic absorption of FILSUVEZ in humans is low following topical administration of FILSUVEZ, and maternal use is not expected to result in fetal exposure to the drug [see Pharmacokinetics (12.3) ] . The background risk of major birth defects and miscarriage for the indicated population is 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. Data Animal Data In an embryofetal development study, birch triterpenes were orally administered to pregnant rats at doses of 10, 30, or 100 mg/kg/day during the period of organogenesis. Birch triterpenes did not cause maternal toxicity or fetal malformations at doses up to 100 mg/kg/day. In a prenatal and postnatal development study, birch triterpenes were orally administered to pregnant rats at doses of 10, 30, or 100 mg/kg/day from gestation day 5 through lactation day 20. Birch triterpenes did not affect development at doses up to 100 mg/kg/day. The available data do not support relevant comparisons of systemic birch triterpenes exposures achieved in the animal studies to exposures observed in humans after topical use of FILSUVEZ.

8.2 Lactation Risk Summary There are no data on the presence of birch triterpenes or metabolites in human milk, the effects on the breastfed infant, or the effect on milk production. No effects on the breastfed infant are anticipated since the systemic exposure of the breastfeeding woman to FILSUVEZ would be low. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for FILSUVEZ and any potential adverse effects on the breastfed infant from FILSUVEZ or from the underlying maternal condition [see Pharmacokinetics (12.3) ].

8.4 Pediatric Use The safety and effectiveness of FILSUVEZ for the treatment of wounds associated with dystrophic and junctional EB have been established in pediatric patients 6 months of age and older. Use of FILSUVEZ in this age group is supported by evidence from a single randomized, placebo-controlled trial in 156 subjects 6 months to 17 years of age [see Clinical Studies (14) ] . The safety and effectiveness of FILSUVEZ have not been established in pediatric patients younger than 6 months of age.

8.5 Geriatric Use Clinical studies of FILSUVEZ did not include sufficient numbers of EB subjects 65 years of age and older to determine whether they respond differently from younger subjects.

Risk Summary There are no available data with use of FILSUVEZ in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In an animal reproduction study, oral administration of birch triterpenes to pregnant rats during the period of organogenesis had no effects on reproductive or fetal parameters (see Data ) . Systemic absorption of FILSUVEZ in humans is low following topical administration of FILSUVEZ, and maternal use is not expected to result in fetal exposure to the drug [see Pharmacokinetics (12.3) ] . The background risk of major birth defects and miscarriage for the indicated population is 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. Data Animal Data In an embryofetal development study, birch triterpenes were orally administered to pregnant rats at doses of 10, 30, or 100 mg/kg/day during the period of organogenesis. Birch triterpenes did not cause maternal toxicity or fetal malformations at doses up to 100 mg/kg/day. In a prenatal and postnatal development study, birch triterpenes were orally administered to pregnant rats at doses of 10, 30, or 100 mg/kg/day from gestation day 5 through lactation day 20. Birch triterpenes did not affect development at doses up to 100 mg/kg/day. The available data do not support relevant comparisons of systemic birch triterpenes exposures achieved in the animal studies to exposures observed in humans after topical use of FILSUVEZ.

The safety and effectiveness of FILSUVEZ for the treatment of wounds associated with dystrophic and junctional EB have been established in pediatric patients 6 months of age and older. Use of FILSUVEZ in this age group is supported by evidence from a single randomized, placebo-controlled trial in 156 subjects 6 months to 17 years of age [see Clinical Studies (14) ] . The safety and effectiveness of FILSUVEZ have not been established in pediatric patients younger than 6 months of age.

Clinical studies of FILSUVEZ did not include sufficient numbers of EB subjects 65 years of age and older to determine whether they respond differently from younger subjects.

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

12.1 Mechanism of Action The mechanism of action of FILSUVEZ in the treatment of wounds associated with epidermolysis bullosa is unknown.

12.2 Pharmacodynamics Pharmacodynamics of FILSUVEZ are unknown.

12.3 Pharmacokinetics Absorption Systemic exposure to betulin was assessed in the 66 evaluable subjects aged ≥13 months to ≤52 years with dystrophic and junctional EB in the clinical trial EASE using venous blood sampling and validated liquid chromatography with tandem mass spectrometry assay. Following treatment with FILSUVEZ once daily (n=27), every 2 (n=33) or 3 days (n=4) or once weekly (n=2) for 90 days with a mean treatment area of 12% body surface area or affected wound surface area of 0.11 m 2 at baseline, betulin blood concentrations in 68% subjects (n=45) were below the lower limit of quantification of 10 ng/mL on Day 90. The highest concentrations of betulin in adult and pediatric subjects with a median age of 10 years (range: ≥13 months to <18 years) were 33 ng/mL and 207 ng/mL, respectively, which were observed on Day 90. Distribution Plasma protein binding of betulin in vitro is >99.9 %. Metabolism The in vitro study indicated that incubation of 1 µmol/L betulin with human hepatocytes generated several unidentified phase I and/or phase II metabolites. In vitro, betulin was mainly metabolized by cytochrome P450 (CYP)3A. The relative contribution of CYP3A and phase II metabolizing enzymes in the overall metabolism of betulin has not been fully characterized. Drug Interaction Studies Clinical Studies No clinical studies evaluating the drug interaction potential of FILSUVEZ have been conducted. In Vitro Studies CYP Enzymes: Betulin inhibited CYP3A and CYP2C8 with an IC 50 value of >0.17 µmol/L (75 ng/mL). Betulin up to 10 µmol/L (4427 ng/mL) did not induce CYP 1A2, 2B6, or 3A4. These findings suggest that FILSUVEZ has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A.

The mechanism of action of FILSUVEZ in the treatment of wounds associated with epidermolysis bullosa is unknown.

Pharmacodynamics of FILSUVEZ are unknown.

Absorption Systemic exposure to betulin was assessed in the 66 evaluable subjects aged ≥13 months to ≤52 years with dystrophic and junctional EB in the clinical trial EASE using venous blood sampling and validated liquid chromatography with tandem mass spectrometry assay. Following treatment with FILSUVEZ once daily (n=27), every 2 (n=33) or 3 days (n=4) or once weekly (n=2) for 90 days with a mean treatment area of 12% body surface area or affected wound surface area of 0.11 m 2 at baseline, betulin blood concentrations in 68% subjects (n=45) were below the lower limit of quantification of 10 ng/mL on Day 90. The highest concentrations of betulin in adult and pediatric subjects with a median age of 10 years (range: ≥13 months to <18 years) were 33 ng/mL and 207 ng/mL, respectively, which were observed on Day 90. Distribution Plasma protein binding of betulin in vitro is >99.9 %. Metabolism The in vitro study indicated that incubation of 1 µmol/L betulin with human hepatocytes generated several unidentified phase I and/or phase II metabolites. In vitro, betulin was mainly metabolized by cytochrome P450 (CYP)3A. The relative contribution of CYP3A and phase II metabolizing enzymes in the overall metabolism of betulin has not been fully characterized. Drug Interaction Studies Clinical Studies No clinical studies evaluating the drug interaction potential of FILSUVEZ have been conducted. In Vitro Studies CYP Enzymes: Betulin inhibited CYP3A and CYP2C8 with an IC 50 value of >0.17 µmol/L (75 ng/mL). Betulin up to 10 µmol/L (4427 ng/mL) did not induce CYP 1A2, 2B6, or 3A4. These findings suggest that FILSUVEZ has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A.

, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been performed with FILSUVEZ or birch triterpenes. Birch triterpenes were not genotoxic in the in vitro bacterial mutagenicity (Ames) assay, an in vitro mammalian chromosome aberration assay using human peripheral lymphocytes, or at doses up to 500 mg/kg in an in vivo mouse micronucleus assay. In a fertility and early embryonic development study in rats, birch triterpenes were orally administered at doses of 10, 30, or 100 mg/kg/day from 2 weeks before mating through gestation day 6. Birch triterpenes had no effects on mating or fertility in male or female rats at doses up to 100 mg/kg/day.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Administration Instructions Advise patients (and/or their caregivers or guardians) of the following [see Dosage and Administration (2) ] : Wash hands before and after applying FILSUVEZ or wear gloves for application. Apply a 1 mm layer of FILSUVEZ to the affected wound surface. Do not rub in the gel. Cover the wound with a sterile non-adhesive wound dressing. Alternatively, apply a generous layer of FILSUVEZ directly to the dressing so that the gel is in direct contact with the wound. Apply FILSUVEZ to cleansed wounds at dressing changes until the wound is healed. FILSUVEZ is for topical use only. FILSUVEZ is not for ophthalmic use and should not be applied to mucous membranes. In case of accidental contact, irrigate eyes with water. The sterile tube of topical gel is for one-time use only. Once the tube is opened, use the product immediately. Discard the tube after use, even if there is some topical gel left. Hypersensitivity Reactions Inform patients that local hypersensitivity and skin reactions, including urticaria and dermatitis, have been reported in patients treated with FILSUVEZ. If signs and symptoms of local hypersensitivity or skin reactions occur, instruct patients to discontinue FILSUVEZ immediately and contact their healthcare provider [see Warnings and Precautions (5.1) ].

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.