Anacaulase-Bcdb

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 tongue depressor) of NEXOBRID to a burn wound area of up to 10% BSA in one application in pediatric patients less than 6 years of age. Remove NEXOBRID after 4 hours [see Dosage and Administration ( 2.5 ) ]. A second application of NEXOBRID is not recommended. 2.3 Preparation of Patient and Burn Wound Treatment Area Prepare the wound area as follows: Thoroughly clean the wound to remove any charred tissue, blisters, and any topical products. Apply a dressing soaked with an antibacterial solution to the treatment area for at least 2 hours. Ensure the wound bed is clear of any remnants of topical agents (e.g., silver sulfadiazine, povidone iodine). Apply an ointment skin protectant (e.g., petrolatum) 2 to 3 cm outside of the treatment area to create an ointment barrier. Avoid applying the protectant ointment to the treatment area itself, as this would impede direct contact of NEXOBRID with the eschar. Protect any other open wounds (e.g., laceration, abraded skin, escharotomy incision) with skin protectant ointments or ointment gauze to prevent possible exposure to NEXOBRID. 2.4 Preparation and Application of NEXOBRID Gather the following sterile supplies prior to NEXOBRID preparation and application: Instrument for mixing (e.g., spatula or tongue depressor) Tongue depressor for NEXOBRID application 0.9% Sodium Chloride Irrigation Occlusive film dressing Loose, thick fluffy dressing and bandage Preparation Prepare NEXOBRID at the patient’s bedside within 15 minutes of the intended application. Using aseptic technique, mix NEXOBRID lyophilized powder and gel vehicle as follows: Pour the NEXOBRID lyophilized powder into the gel vehicle jar. Thoroughly mix the NEXOBRID lyophilized powder and gel vehicle using a sterile instrument (e.g., tongue depressor or spatula) until the mixture is uniform. The mixed lyophilized powder and gel vehicle produce NEXOBRID in a final concentration of 8.8% w/w. DISCARD NEXOBRID IF NOT USED WITHIN 15 MINUTES OF PREPARATION, as the enzymatic activity of NEXOBRID decreases progressively following mixing. Application Apply NEXOBRID within 15 minutes of preparation as follows: Moisten the treatment area by sprinkling sterile 0.9% Sodium Chloride Irrigation onto the burn wound. Using a sterile tongue depressor, completely cover the moistened burn wound treatment area with the mixed NEXOBRID in a 3 mm thick layer (approximate thickness of a tongue depressor). Ensure NEXOBRID covers the entire target treatment area. Cover the treated wound with a sterile occlusive film dressing. Gently press the occlusive film dressing at the area of contact with the ointment barrier to ensure adherence between the occlusive film dressing and the ointment barrier and to achieve complete containment of NEXOBRID on the treatment area. There should be no visible air under the occlusive film dressing. Cover the occlusive film dressing with a sterile loose, thick, fluffy dressing and secure with a sterile bandage. Discard any unused portions of NEXOBRID. 2.5 Removal of NEXOBRID Remove NEXOBRID after 4 hours. Gather the following sterile supplies prior to NEXOBRID removal: Blunt-edged instruments (e.g., tongue depressor) Large dry gauze Gauze soaked with 0.9% Sodium Chloride Irrigation Dressing soaked with an antibacterial solution Remove the occlusive film dressing using aseptic technique. Remove the ointment barrier using a sterile blunt-edged instrument. Remove the dissolved eschar from the wound by scraping it away with a sterile blunt-edged instrument. Wipe the wound thoroughly with a large sterile dry gauze, then wipe with a sterile gauze that has been soaked with sterile 0.9% Sodium Chloride Irrigation. Rub the treated area until the appearance of a clean dermis or subcutaneous tissues with pinpoint bleeding. To remove remnants of dissolved eschar, apply a dressing soaked with an antibacterial solution for at least 2 hours. 2.6 Monitoring Monitor patients for signs of local or systemic allergic reactions. If a hypersensitivity reaction occurs, remove NEXOBRID (if applicable) from the treatment area and initiate appropriate therapy [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )].

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 Standard of Care in NEXOBRID-Treated Pediatric Subjects in Study 3 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 NEXOBRID (N = 69) Patients n (%) Standard of Care b (N = 70) Patients n (%) Pruritus 9 (13) 7 (10) Pyrexia 7 (10) 4 (6) Vomiting 5 (7) 3 (4) Nausea 3 (4) 2 (3) Constipation 3 (4) 1 (1) Nasopharyngitis 3 (4) 1 (1) Rash 2 (3) 0 Hemoglobin decreased 2 (3) 0 Rhinovirus 2 (3) 0 Ear Infection 2 (3) 0 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of anacaulase-bcdb outside of 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. Immune system disorders: Hypersensitivity, including anaphylaxis and urticaria

12.3 Pharmacokinetics Absorption For adults and pediatric subjects 4 years of age and older, NEXOBRID applied to deep partial and full thickness burn wounds is absorbed, with median serum T max of 4 hours (during the treatment application). Systemic exposure (i.e., AUC) of bromelain, a component of anacaulase-bcdb is correlated with the size of the treated area and NEXOBRID dose, but not the depth of the burn wound. The systemic exposure in pediatric subjects was comparable to adults. In adult subjects, C max and the dose‑normalized C max values after the first and second application (mean dosing interval of 17 hours) are comparable and only slight accumulation (less than 2-fold difference) is seen in AUC 0-4 and AUC 0-4 dose‑normalized levels after the second application, compared to the first application. Elimination A majority of adults and pediatric subjects had no quantifiable serum concentrations after 72 hours. The mean ± SD terminal half-life of bromelain, a component of anacaulase-bcdb, is 12 ± 4.4 hours. Drug Interaction Studies Effect of NEXOBRID on Other Drugs Bromelain, a component of anacaulase-bcdb, exhibited CYP2C8 time-dependent inhibition in human hepatocytes and inhibited human microsomal CYP2C9. No clinical studies have been conducted to assess the potential for systemic drug interactions.