NEXOBRID

1 INDICATIONS AND USAGE NEXOBRID is indicated for eschar removal in adults and pediatric patients with deep partial thickness (DPT) and/or full thickness (FT) thermal burns. Limitations of Use The safety and effectiveness of NEXOBRID have not been established for treatment of: Chemical or electrical burns Burns on the face, perineum, or genitalia Burns on the feet of patients with diabetes mellitus or on the feet of patients with occlusive vascular disease Circumferential burns Burns in patients with significant cardiopulmonary disease, including inhalation injury NEXOBRID is not recommended for: Wounds contaminated with radioactive and other hazardous substances to avoid unforeseeable reactions with the product and an increased risk of spreading the noxious substance. Treatment of burn wounds where medical devices (e.g., implants, pacemakers, shunts) or vital structures (e.g., large vessels) could become exposed during eschar removal. NEXOBRID contains proteolytic enzymes and is indicated for eschar removal in adults and pediatric patients with deep partial thickness and/or full thickness thermal burns ( 1 ). Limitations of Use The safety and effectiveness of NEXOBRID have not been established for treatment of: Chemical or electrical burns ( 1 ). Burns on the face, perineum, or genitalia ( 1 ). Burns on the feet of patients with diabetes mellitus or on the feet of patients with occlusive vascular disease ( 1 ). Circumferential burns ( 1 ). Burns in patients with significant cardiopulmonary disease, including inhalation injury ( 1 ). NEXOBRID is not recommended for: Wounds contaminated with radioactive and other hazardous substances to avoid unforeseeable reactions with the product and an increased risk of spreading the noxious substance ( 1 ) Treatment of burn wounds where medical devices (e.g., implants, pacemakers, shunts) or vital structures (e.g., large vessels) could become exposed during eschar removal ( 1 ).

2 DOSAGE AND ADMINISTRATION NEXOBRID lyophilized powder and gel vehicle must be mixed prior to administration ( 2.1 ). Use 2 g of Nexobrid lyophilized powder mixed with 20 g gel for treatment of up to 180 cm2 of treated burn area; or 5 g of Nexobrid lyophilized powder mixed with 50 g gel for treatment of up to 450 cm2 of treated burn area ( 2.1 ). For topical use only ( 2.1 ). Dosage in Adults: Apply a 3 mm thick layer of NEXOBRID in one application to an area of up to 15% body surface area (BSA) for four hours. A second application may be applied 24 hours later. For both applications, the total treated area must not exceed 20% BSA ( 2.2 ). Dosage in Pediatric Patients 6 Years of Age and Older: Apply a 3 mm thick layer of NEXOBRID in one application of 4 hours to an area of up to 15% BSA ( 2.2 ). Dosage in Pediatric Patients Less Than 6 Years of Age: Apply a 3 mm thick layer of NEXOBRID in one application of 4 hours to an area of up to 10% BSA ( 2.2 ). Prepare NEXOBRID at patient’s bedside within 15 minutes of intended application ( 2.4 ). Apply NEXOBRID to a clean, moist wound bed free of burned epidermis layer and blisters, and cover with an occlusive film dressing ( 2.3 , 2.4 ). See Full Prescribing Information for additional details on preparation, administration, and removal of NEXOBRID ( 2.5 , 2.6 ). 2.1 Important Administration Information NEXOBRID is only to be administered by a healthcare provider. Take precautions to avoid exposure to NEXOBRID during preparation and handling (e.g., use gloves, surgical masks, other protective coverings, as needed) [see Warnings and Precautions ( 5.1 )] . Use pain management as practiced for an extensive dressing change of burn wounds 15 minutes prior to and throughout all NEXOBRID-related procedures. NEXOBRID is available as: 2 g of lyophilized powder (containing 1.94 grams of anacaulase-bcdb) with a 20 g gel vehicle, for treatment of up to 180 cm 2 of burn area after mixing. 5 g lyophilized powder (containing 4.85 grams of anacaulase-bcdb) with a 50 g gel vehicle, for treatment of up to 450 cm 2 of burn area after mixing. NEXOBRID lyophilized powder and gel vehicle must be mixed no more than 15 minutes prior to administration. Discard NEXOBRID if not used within 15 minutes of preparation, as the enzymatic activity of the product decreases progressively following mixing. Each vial of lyophilized powder, jar of gel vehicle, and the mixed NEXOBRID are for use for only one patient and for one application [see Dosage and Administration ( 2.4 )] . NEXOBRID is for topical use only. Apply an ointment skin protectant around the treatment area to create an ointment barrier [see Dosage and Administration ( 2.3 )]. 2.2 Recommended Dosage Recommended Dosage in Adults Apply a 3 mm thick layer (approximate thickness of a tongue depressor) of NEXOBRID to a burn wound area of up to 15% body surface area (BSA) in one application in adult patients. Remove NEXOBRID after 4 hours [see Dosage and Administration ( 2.5 )] . A second application of NEXOBRID may be applied 24 hours following the first application to either the same area previously treated with NEXOBRID or to a new area in adult patients. Apply a second application if: The wound area is more than 15% BSA, or Multiple wound areas on different body surfaces require two treatments for logistical reasons such as body position, or The first application's eschar removal was not complete. For both applications, the total treated area must not exceed 20% BSA. Recommended Dosage in Pediatric Patients Pediatric Patients 6 Years of Age and Older Apply a 3 mm thick layer (approximate thickness of a tongue depressor) of NEXOBRID to a burn wound area of up to 15% BSA in one application in pediatric patients 6 years of age and older. Remove NEXOBRID after 4 hours [see Dosage and Administration ( 2.5 )] . A second application of NEXOBRID is not recommended. Pediatric Patients Less Than 6 Years of Age Apply a 3 mm thick layer (approximate thickness of a tongu …

3 DOSAGE FORMS AND STRENGTHS For topical gel: 8.8%; off-white to light tan lyophilized powder in a glass vial to be mixed in a clear and colorless gel vehicle in a glass jar. For topical gel: 8.8% ( 3 ).

4 CONTRAINDICATIONS NEXOBRID is contraindicated in patients with [see Warnings and Precautions ( 5.1 ), Description ( 11 )] : Known hypersensitivity to anacaulase-bcdb, bromelain, pineapples, or to any of the other components. Known hypersensitivity to papayas or papain because of the risk of cross-sensitivity. Known hypersensitivity to anacaulase-bcdb, bromelain, pineapples, or to any of the other components ( 4 ). Known hypersensitivity to papayas or papain because of the risk of cross-sensitivity ( 4 ).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] The most common adverse reactions (>10%) were pruritus and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Vericel Corporation at 1-888-454-BURN 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 product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice. Adults: Studies 1 and 2 evaluated subjects undergoing eschar removal for deep partial thickness (DPT) and/or full thickness (FT) thermal burns [see Clinical Studies ( 14 )] . An integrated analysis of safety data from Studies 1 and 2 compared NEXOBRID (n=177) to standard of care (SOC) (n=149). The SOC treatment included both surgical and non-surgical eschar removal methods. The mean age of the safety population was 35.6 years; 73% were male; 81% were White, 9% were Black, 6% were other races, and 3% were Asian. Regarding burn etiology, 65% had fire/flame burns, 26% had scald burns, 8% had contact burns, and <1% had burns of other etiology. The mean body surface area (BSA) of wounds that received study treatment was 9.2±5.07%. Mean BSA of all burn wounds was 12.0±6.05%. Of the 177 subjects who were treated with NEXOBRID in Studies 1 and 2, 159 (90%) received one treatment of NEXOBRID, and 18 (10%) received 2 treatments. Table 1 presents adverse reactions that occurred in ≥ 1% of subjects in the NEXOBRID arm and at a higher incidence than the SOC arm, up to 3 months following wound closure. Table 1: Adverse Reactions Reported in ≥1% and Greater Incidence than Standard of Care in NEXOBRID-Treated Patients in Studies 1 and 2 a a During the time period from baseline to 3 months post wound closure b Standard of Care treatment included both surgical and non-surgical eschar removal methods c Wound complication includes skin graft failure, graft loss, graft complication, and wound decomposition NEXOBRID (N = 177) Patients n (%) Standard of Care b (N = 149) Patients n (%) Pruritus 27 (15) 19 (13) Pyrexia 21 (12) 13 (9) Wound complication c 15 (9) 9 (6.0) Anemia 11 (6) 8 (5) Vomiting 9 (5) 4 (3) Insomnia 8 (5) 6 (4) Urinary tract infection 7 (4) 1 (1) Tachycardia 5 (3) 0 Rash 6 (3) 0 Infection 4 (2) 2 (1) Sepsis 4 (2) 1 (1) Leukocytosis 3 (2) 1 (1) Hypotension 3 (2) 1 (1) Hepatic function abnormal 2 (1) 0 Drug hypersensitivity 2 (1) 0 Bacteremia 2 (1) 0 Scar 2 (1) 0 Subcutaneous hematoma 2 (1) 0 Decubitus ulcer 2 (1) 0 Pediatric Subjects: Study 3 (CIDS study) evaluated pediatric subjects undergoing eschar removal for deep partial thickness (DPT) and/or full thickness (FT) thermal burns [see Clinical Studies (14)]. A total of 139 subjects (69 NEXOBRID, 70 SOC) were treated in the study. The SOC treatment included both surgical and non-surgical eschar removal methods. The mean age was comparable in the NEXOBRID (5.89 years) and SOC (5.75 years) arms. The majority of subjects were male (59% NEXOBRID, 69% SOC). For race, 70% NEXOBRID and 69% SOC subjects were White, 25% NEXOBRID and 23% SOC subjects were Asian, 4% NEXOBRID and 3% SOC subjects were Black or African American, and 1% NEXOBRID and 4% SOC subjects were other races. For ethnicity, 4% NEXOBRID and 10% SOC subjects identified as Hispanic or Latino. The majority of burns in both treatment arms (NEXOBRID and SOC) were due to scald (68% and 67%). The majority of patients in both treatment groups (NEXOBRID and SOC) had 1 treated wound (71% and 80%, respectively). Table 2 presents adverse reactions that occurred in ≥ 1% of subjects in the NEXOBRID arm and at a higher incidence than the SOC arm, up to 3 months following wound closure. Table 2: Adverse Reactions Reported in ≥1% and Greater Incidence than Sta …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on NEXOBRID use in pregnant women to evaluate for a drug associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 embryofetal developmental studies in rats and rabbits, intravenous doses up to 4 and 0.1 mg/kg/day NEXOBRID were administered to pregnant rats and rabbits, respectively, during organogenesis. No significant developmental toxicities were observed in these studies. However, severe maternal toxicities were noted and the tolerable maternal exposure levels were much lower compared with the maximum human exposure in clinical setting. 8.2 Lactation Risk Summary There are no data on the presence of anacaulase-bcdb in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NEXOBRID and any potential adverse effects on the breastfed infant from NEXOBRID or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of NEXOBRID for eschar removal have been established in pediatric patients with deep partial thickness and/or full thickness thermal burns. Use of NEXOBRID for this indication is supported by evidence from one adequate and well-controlled trial in 69 pediatric subjects treated with NEXOBRID [see Clinical Studies ( 14 )] . 8.5 Geriatric Use Of the 177 subjects exposed to NEXOBRID for eschar removal in deep partial thickness (DPT) and/or full thickness (FT) thermal burns, 6 (3%) subjects were 65 years or older, and 1 (< 1%) subject was 75 years or older [see Clinical Studies ( 14 )] . Clinical trials of NEXOBRID did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

12.1 Mechanism of Action The mixture of enzymes in NEXOBRID dissolves burn wound eschar. The specific components responsible for this effect have not been identified.

11 DESCRIPTION The drug substance in NEXOBRID, anacaulase-bcdb, is a mixture of proteolytic enzymes extracted from the stems of pineapple plants ( Ananas comosus [L.] Merr.) that has been sterile filtered and lyophilized. The drug substance, anacaulase-bcdb, is composed mainly (80% to 95% w/w) of the proteins: stem bromelain, ananain, jacalin-like lectin, bromelain inhibitors, and phytocystatin inhibitor; and saccharides, as both free monosaccharides and the N-linked glycan of stem bromelain, and small molecule metabolites. The drug substance includes inactive buffer components containing acetic acid, ammonium sulfate, and Water for Injection. Each gram of lyophilized powder contains 0.97 grams of anacaulase-bcdb. NEXOBRID (anacaulase-bcdb) for topical gel is a botanical drug product supplied as a sterile, preservative-free, lyophilized powder in a single-dose glass vial that must be mixed in a gel vehicle supplied in a single-dose glass jar prior to application. Mixture of either 2 grams of lyophilized powder (containing 1.94 grams of anacaulase-bcdb) or 5 grams of lyophilized powder (containing 4.85 grams of anacaulase-bcdb) in 20 grams or 50 grams of gel vehicle, respectively, provides an 8.8% w/w, yellowish white to light brown opaque gel for topical use. The pH of the topical gel mixture is approximately 6.2 to 6.7. The co-packaged 20 gram or 50 gram jar of the sterile, preservative-free gel vehicle contains carbomer 980, dibasic sodium phosphate, sodium hydroxide, and Water for Injection.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied NEXOBRID (anacaulase-bcdb) for topical gel, 8.8%, is supplied as a package containing two components, a sterile, preservative-free, off-white to light tan lyophilized powder in a glass vial and a sterile, preservative-free, clear and colorless gel vehicle in a glass jar, that are mixed prior to application [see Dosage and Administration ( 2.4 )] . NEXOBRID is available: One glass vial of 2 g lyophilized powder (containing 1.94 grams of anacaulase-bcdb) and one glass jar of 20 g gel vehicle per carton (NDC 69866-2002-3) One glass vial of 5 g lyophilized powder (containing 4.85 grams of anacaulase-bcdb) and one glass jar of 50 g gel vehicle per carton (NDC 69866-2005-3) Storage and Handling Store and transport NEXOBRID package upright and refrigerated at 2°C to 8°C (36 °F to 46 °F) in the original carton to protect from light. DO NOT FREEZE. Do not use if the vial or jar are damaged.