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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions : Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarketing use of anacaulase-bcdb. If a hypersensitivity reaction occurs, remove NEXOBRID (if applicable) and initiate appropriate therapy ( 5.1 ). Coagulopathy: Avoid use of NEXOBRID in patients with uncontrolled disorders of coagulation. Use with caution in patients on anticoagulant therapy or other drugs affecting coagulation, and in patients with low platelet counts and increased risk of bleeding from other causes. Monitor patients for possible signs of coagulation abnormalities and signs of bleeding ( 5.2 ). 5.1 Hypersensitivity Reactions NEXOBRID-Treated Patients Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarketing use of NEXOBRID. If a hypersensitivity reaction occurs, remove NEXOBRID (if applicable) and initiate appropriate therapy. NEXOBRID is contraindicated in patients with a known hypersensitivity to anacaulase- bcdb, bromelain, pineapples or to any other component of NEXOBRID. NEXOBRID is also contraindicated in patients with known hypersensitivity to papayas or papain because of the risk of cross-sensitivity. Healthcare Providers Preparing and Applying NEXOBRID Healthcare personnel should take appropriate precautions to avoid exposure when preparing and handling NEXOBRID (e.g., gloves, surgical masks, other protective coverings, as needed). In the event of inadvertent skin exposure, rinse NEXOBRID off with water to reduce the likelihood of skin sensitization. 5.2 Coagulopathy A reduction of platelet aggregation and plasma fibrinogen levels and a moderate increase in partial thromboplastin and prothrombin times have been reported in the literature as possible effects following oral administration of bromelain, a component of NEXOBRID. In vitro and animal data suggest that bromelain can also promote fibrinolysis. Avoid use of NEXOBRID in patients with uncontrolled disorders of coagulation. Use NEXOBRID with caution in patients on anticoagulant therapy or other drugs affecting coagulation, and in patients with low platelet counts and increased risk of bleeding from other causes (e.g., peptic ulcers and sepsis). Monitor patients for possible signs of coagulation abnormalities and signs of bleeding.
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